Stefanie Dimmeler

Publications of Stefanie Dimmeler

• Sustained delivery of SDF-1α from heparin-based hydrogels to attract circulating pro-angiogenic cells.

  Authors: Silvana Prokoph, Emmanouil Chavakis, Kandice R Levental, Andrea Zieris, Uwe Freudenberg, Stefanie Dimmeler, Carsten Werner

  Biomaterials. 04/2012;

  Enrichment of progenitor cells in ischemic tissue has become a promising therapeutic strategy in the treatment of myocardial infarction. Towards this aim, we report a biology-inspired concept usingEnrichment of progenitor cells in ischemic tissue has become a promising therapeutic strategy in the treatment of myocardial infarction. Towards this aim, we report a biology-inspired concept using sulfated glycosaminoglycans to sustainably generate chemokine gradients for the localized accumulation of early endothelial progenitor cells (eEPCs). StarPEG-heparin hydrogels, which have been previously demonstrated to support angiogenesis, were functionalized with SDF-1α, a potent chemoattractant known to act on EPCs. The gels were quantitatively shown to release the chemokine in amounts that are adjustable by the choice of loading concentrations and by matrix metalloprotease (MMP) mediated hydrogel cleavage. Transwell assays confirmed significantly enhanced migration of early EPCs towards concentration gradients of hydrogel-delivered SDF-1αin vitro. Subcutaneous implantation of SDF-1α-releasing gels in mice resulted in massive infiltration of early EPCs and subsequently improved vascularization. In conclusion, sustained delivery of SDF-1α from pro-angiogenic starPEG-heparin hydrogels can effectively attract early EPCs, offering a powerful means to trigger endogenous mechanisms of cardiac regeneration.

• MicroRNAs and Stem Cells: Control of Pluripotency, Reprogramming, and Lineage Commitment.

  Authors: Eva-Marie Heinrich, Stefanie Dimmeler

  Circulation research. 03/2012; 110(7):1014-22.

  Stem cells hold great promise for regenerative medicine and the treatment of cardiovascular diseases. The mechanisms regulating self-renewal, pluripotency, and differentiation are not fullyStem cells hold great promise for regenerative medicine and the treatment of cardiovascular diseases. The mechanisms regulating self-renewal, pluripotency, and differentiation are not fully understood. MicroRNAs (miRs) are small noncoding RNAs controlling gene expression, either by inducing mRNA degradation or by blocking mRNA translation. The expression of miRs was shown to regulate various aspects of stem cell functions, including the maintenance and induction of pluripotency for reprogramming. In addition, some miRs control cell fate decisions. This review summarizes the role of miRs in reprogramming and embryonic stem cell self-renewal, and specifically addresses the regulation of cardiovascular cell fate decisions by miRs.

• Nox4 Is a Protective Reactive Oxygen Species Generating Vascular NADPH Oxidase.

  Authors: Katrin Schröder, Min Zhang, Sebastian Benkhoff, Anja Mieth, Rainer Pliquett, Judith Kosowski, Christoph Kruse, Peter Lüdike, U Ruth Michaelis, Norbert Weissmann, Stefanie Dimmeler, Ajay M Shah, Ralf P Brandes

  Circulation research. 03/2012;

  Rationale:The function of Nox4, a source of vascular H(2)O(2), is unknown. Other Nox proteins were identified as mediators of endothelial dysfunction.Objective:We determined the function of Nox4 inRationale:The function of Nox4, a source of vascular H(2)O(2), is unknown. Other Nox proteins were identified as mediators of endothelial dysfunction.Objective:We determined the function of Nox4 in situations of increased stress induced by ischemia or angiotensin II with global and tamoxifen-inducible Nox4(-/-) mice.Methods and Results:Nox4 was highly expressed in the endothelium and contributed to H(2)O(2) formation. Nox4(-/-) mice exhibited attenuated angiogenesis (femoral artery ligation) and PEG-catalase treatment in control mice had a similar effect. Tube formation in cultured Nox4(-/-) lung endothelial cells (LECs) was attenuated and restored by low concentrations of H(2)O(2,) whereas PEG-catalase attenuated tube formation in control LECs. Angiotensin II infusion was used as a model of oxidative stress. Compared to wild-type, aortas from inducible Nox4-deficient animals had development of increased inflammation, media hypertrophy, and endothelial dysfunction. Mechanistically, loss of Nox4 resulted in reduction of endothelial nitric oxide synthase expression, nitric oxide production, and heme oxygenase-1 (HO-1) expression, which was associated with apoptosis and inflammatory activation. HO-1 expression is controlled by Nrf-2. Accordingly, Nox4-deficient LECs exhibited reduced Nrf-2 protein level and deletion of Nox4 reduced Nrf-2 reporter gene activity. In vivo treatment with hemin, an inducer of HO-1, blocked the vascular hypertrophy induced by Nox4 deletion in the angiotensin II infusion model and carbon monoxide, the product of HO-1, blocked the Nox4-deletion-induced apoptosis in LECs.Conclusion:Endogenous Nox4 protects the vasculature during ischemic or inflammatory stress. Different from Nox1 and Nox2, this particular NADPH oxidase therefore may have a protective vascular function.

• Paracrine Regulation of Cardiac miRNAs by Bone Marrow Mononuclear Cell Therapy in Myocardial Infarction.

  Authors: Kazuma Iekushi, Florian Seeger, Birgit Assmus, Andreas M Zeiher, Stefanie Dimmeler

  Circulation. 03/2012;

  BACKGROUND: Cell therapy with bone marrow-derived mononuclear cells (BMC) can improve recovery of cardiac function after ischemia, however, the molecular mechanisms are not yet fully understood.BACKGROUND: Cell therapy with bone marrow-derived mononuclear cells (BMC) can improve recovery of cardiac function after ischemia, however, the molecular mechanisms are not yet fully understood. MicroRNAs (miRNAs) are key regulators of gene expression and modulate the pathophysiology of cardiovascular diseases. METHODS AND RESULTS: We demonstrated that intramyocardial delivery of BMC in infarcted mice regulates the expression of cardiac miRNAs and significantly down-regulates the pro-apoptotic miR-34a. In vitro studies confirmed that the supernatant of BMC inhibited the expression of H(2)O(2)-induced miR-34a and cardiomyocytes apoptosis. These effects were blocked by neutralizing antibodies directed against insulin growth factor-1 (IGF-1). Indeed, IGF-1 significantly inhibited H(2)O(2)-induced miR-34a expression, and miR-34a overexpression abolished the anti-apoptotic effect of IGF-1. Likewise, inhibition of IGF-1 signaling in vivo abolished the BMC-mediated inhibition of miR-34 expression and the protective effect on cardiac function and increased apoptosis and cardiac fibrosis. IGF-1 specifically blocked the expression of the precursor and the mature miR-34a, but did not interfere with the transcription of the primary miR-34a demonstrating that IGF-1 blocks the processing of miR-34a. CONCLUSIONS: Together, our data demonstrate that the paracrine regulation of cardiac miRNAs by transplanted BMC contributes to the protective effects of cell therapy. BMC release IGF-1, which inhibits the processing of miR-34a, thereby blocking cardiomyocyte apoptosis.

• Pressure overload leads to an increase of cardiac resident stem cells.

  Authors: Stefan Rupp, Jürgen Bauer, Susanne von Gerlach, Stephan Fichtlscherer, Andreas M Zeiher, Stefanie Dimmeler, Dietmar Schranz

  Basic research in cardiology. 03/2012; 107(2):252.

  Recent studies suggest that the mammalian heart possesses some capacity for cardiac regeneration. This regenerative capacity is primarily documented postnatally and after myocardial infarction orRecent studies suggest that the mammalian heart possesses some capacity for cardiac regeneration. This regenerative capacity is primarily documented postnatally and after myocardial infarction or pressure overload. Although the cell type that mediates endogenous regeneration is unclear, cardiac stem cells might be considered as potential candidates. To determine the number of c-kit + cardiac resident cells under conditions of pressure overload, we evaluated specimens derived from n = 8 patients with pressure overloaded single right ventricles in comparison to n = 4 explanted hearts from patients with dilated cardiomyopathy and n = 14 biopsies from children after heart transplantation. The age of the patients ranged from 16 days to 19 years. For quantification of cardiac stem cells, c-kit+/mast cell tryptase-/CD45- cells were counted and expressed as percent of the total nuclei. In specimens from patients with dilated cardiomyopathy, 0.13 ± 0.09% c-kit +/mast cell tryptase-/CD45- cells were detected. However, in specimens from patients with pressure overloaded single right ventricles, the numbers of c-kit+/mast cell tryptase-/CD45- cells were significantly higher (0.41 ±0.24%, p < 0.05). Under conditions of pressure overload, the right ventricle shows an approximately three-fold increase in c-kit+/mast cell tryptase-/CD45- cardiac resident cells. Despite the fact that this increased number of c-kit+ cells is not sufficient to prevent the failing heart from congestive heart failure, understanding the mechanism that leads to an increase of presumably cardiac resident stem cells under conditions of pressure overload might help to develop new strategies to enhance endogenous repair.

• Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use.

  Authors: Gian Paolo Fadini, Douglas Losordo, Stefanie Dimmeler

  Circulation research. 02/2012; 110(4):624-37.

  Diverse subsets of endothelial progenitor cells (EPCs) are used for the treatment of ischemic diseases in clinical trials, and circulating EPCs levels are considered as biomarkers for coronary andDiverse subsets of endothelial progenitor cells (EPCs) are used for the treatment of ischemic diseases in clinical trials, and circulating EPCs levels are considered as biomarkers for coronary and peripheral artery disease. However, despite significant steps forward in defining their potential for both therapeutic and diagnostic purposes, further progress has been mired by unresolved questions around the definition and the mechanism of action of EPCs. Diverse culturing methods and detection of various combinations of different surface antigens were used to enrich and identify EPCs. These attempts were particularly challenged by the close relationship and overlapping markers of the endothelial and hematopoietic lineages. This article will critically review the most commonly used protocols to define EPCs by culture assays or by fluorescence-activated cell sorter in the context of their therapeutic or diagnostic use. We also delineate new research avenues to move forward our knowledge on EPC biology.

• Intracoronary bone marrow cell application for terminal heart failure in children.

  Authors: Stefan Rupp, Christian Jux, Halvard Bönig, Jürgen Bauer, Torsten Tonn, Erhard Seifried, Stefanie Dimmeler, Andreas M Zeiher, Dietmar Schranz

  Cardiology in the young. 02/2012;

  IntroductionIn spite of tremendous progress in the medical and surgical treatment of children with congenital heart disease and dilated cardiomyopathy achieved during the past few decades, for someIntroductionIn spite of tremendous progress in the medical and surgical treatment of children with congenital heart disease and dilated cardiomyopathy achieved during the past few decades, for some children a heart transplant remains the only option. Clinically relevant benefits of intracoronary injection of autologous stem cells on cardiac function and remodelling have been demonstrated in adult patients with acute myocardial infarction. Experience with autologous stem cell therapy in children with severe congenital or acquired pump failure is limited to a small number of case reports.Method and resultsBetween 2006 and 2010, nine severely ill children were treated with intracoronary infusion of autologous bone marrow-derived mononuclear cells as part of a compassionate therapy in our centre. No procedure-related unexpected adverse events occurred. There was one patient on extracorporeal membrane oxygenation who died of haemorrhage unrelated to the procedure; three patients proceeded to heart transplantation once a donor heart became available. The other five patients showed an improvement with respect to New York Heart Association classification (greater than or equal to 1), brain natriuretic peptide serum levels, and ejection fraction.ConclusionSimilar to adults, intracoronary injection of autologous bone marrow cell is technically feasible and safe for children. On the basis of our data, we propose to perform a pilot study for children with congestive heart failure, to formally assess the efficacy of intracoronary autologous bone marrow cell therapy.

• Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs.

  Authors: Eduard Hergenreider, Susanne Heydt, Karine Tréguer, Thomas Boettger, Anton J G Horrevoets, Andreas M Zeiher, Margot P Scheffer, Achilleas S Frangakis, Xiaoke Yin, Manuel Mayr, Thomas Braun, Carmen Urbich, Reinier A Boon, Stefanie Dimmeler

  Nature cell biology. 01/2012; 14(3):249-56.

  The shear-responsive transcription factor Krüppel-like factor 2 (KLF2) is a critical regulator of endothelial gene expression patterns induced by atheroprotective flow. As microRNAs (miRNAs)The shear-responsive transcription factor Krüppel-like factor 2 (KLF2) is a critical regulator of endothelial gene expression patterns induced by atheroprotective flow. As microRNAs (miRNAs) post-transcriptionally control gene expression in many pathogenic and physiological processes, we investigated the regulation of miRNAs by KLF2 in endothelial cells. KLF2 binds to the promoter and induces a significant upregulation of the miR-143/145 cluster. Interestingly, miR-143/145 has been shown to control smooth muscle cell (SMC) phenotypes; therefore, we investigated the possibility of transport of these miRNAs between endothelial cells and SMCs. Indeed, extracellular vesicles secreted by KLF2-transduced or shear-stress-stimulated HUVECs are enriched in miR-143/145 and control target gene expression in co-cultured SMCs. Extracellular vesicles derived from KLF2-expressing endothelial cells also reduced atherosclerotic lesion formation in the aorta of ApoE(-/-) mice. Combined, our results show that atheroprotective stimuli induce communication between endothelial cells and SMCs through an miRNA- and extracellular-vesicle-mediated mechanism and that this may comprise a promising strategy to combat atherosclerosis.

• MicroRNA-27a/b controls endothelial cell repulsion and angiogenesis by targeting semaphorin 6A.

  Authors: Carmen Urbich, David Kaluza, Timo Frömel, Andrea Knau, Katrin Bennewitz, Reinier A Boon, Angelika Bonauer, Carmen Doebele, Jes-Niels Boeckel, Eduard Hergenreider, Andreas M Zeiher, Jens Kroll, Ingrid Fleming, Stefanie Dimmeler

  Blood. 12/2011; 119(6):1607-16.

  MicroRNAs (miRs) are small RNAs that regulate gene expression at the posttranscriptional level. miR-27 is expressed in endothelial cells, but the specific functions of miR-27b and its family memberMicroRNAs (miRs) are small RNAs that regulate gene expression at the posttranscriptional level. miR-27 is expressed in endothelial cells, but the specific functions of miR-27b and its family member miR-27a are largely unknown. Here we demonstrate that overexpression of miR-27a and miR-27b significantly increased endothelial cell sprouting. Inhibition of both miR-27a and miR-27b impaired endothelial cell sprout formation and induced endothelial cell repulsion in vitro. In vivo, inhibition of miR-27a/b decreased the number of perfused vessels in Matrigel plugs and impaired embryonic vessel formation in zebrafish. Mechanistically, miR-27 regulated the expression of the angiogenesis inhibitor semaphorin 6A (SEMA6A) in vitro and in vivo and targeted the 3'-untranslated region of SEMA6A. Silencing of SEMA6A partially reversed the inhibition of endothelial cell sprouting and abrogated the repulsion of endothelial cells mediated by miR-27a/b inhibition, indicating that SEMA6A is a functionally relevant miR-27 downstream target regulating endothelial cell repulsion. In summary, we show that miR-27a/b promotes angiogenesis by targeting the angiogenesis inhibitor SEMA6A, which controls repulsion of neighboring endothelial cells.

• Acute myocardial infarction activates progenitor cells and increases Wnt signalling in the bone marrow.

  Authors: Birgit Assmus, Masayoshi Iwasaki, Volker Schächinger, Tino Roexe, Masamichi Koyanagi, Kazuma Iekushi, Quanfu Xu, Torsten Tonn, Erhard Seifried, Stefan Liebner, Wolfgang Tilman Kranert, Frank Grünwald, Stefanie Dimmeler, Andreas M Zeiher

  European heart journal. 12/2011;

  AimsWe aimed to characterize the influence of acute myocardial infarction (AMI) on the metabolic activity of the bone marrow (BM) and on the composition and functional activity of BM-derivedAimsWe aimed to characterize the influence of acute myocardial infarction (AMI) on the metabolic activity of the bone marrow (BM) and on the composition and functional activity of BM-derived mononuclear cells (BMC). Acute ischaemia or other stressors induce the mobilization of progenitor cells from the BM stem cell niche. The effect of AMI on the numbers and functional activity of cells within the BM is unknown.Methods and resultsIn patients of the REPAIR-AMI trial as well as in mice, the number and functionality of BMC was compared with respect to the time interval from AMI. Activation of Wnt signalling was assessed after AMI induction in TOP-GAL transgenic reporter mice, carrying a β-galactosidase gene driven by an LEF/TCF/β-catenin responsive promoter. The metabolic activity of the BM, as determined by F-18-fluorodeoxyglucose-positron emission tomography, was significantly higher in patients with AMI compared with patients with chronic post-ischaemic heart failure. Moreover, the number of haematopoietic CD34(+) (P < 0.05) and CD133(+) (P < 0.05) cells in the BM aspirates was significantly increased in patients within 7 days after AMI. In order to confirm these clinical data, we induced AMI in mice, which time-dependently increased the number of c-kit + Sca-1 + lin- cells and colony-forming units in the BM. Activation of the BM by AMI induced a significant increase in Wnt signalling, which is known to induce proliferation of haematopoietic stem cells, and demonstrated increased levels of the Wnt target Axin-2 in BM-derived cells on Day 7 (P < 0.01 vs. control).ConclusionAcute myocardial infarction is associated with an increased metabolic activity and increased levels of progenitor cells within days after AMI. These findings document an activation of the stem cell niche within the BM following AMI, which may have important implications for the optimal timing of cell aspirations used for therapeutic application in patients with AMI.

• Inhibition of MicroRNA-17 Improves Lung and Heart Function in Experimental Pulmonary Hypertension.

  Authors: Soni S Pullamsetti, Carmen Doebele, Ariane Fischer, Rajkumar Savai, Baktybek Kojonazarov, Bhola K Dahal, Hossein A Ghofrani, Norbert Weissmann, Friedrich Grimminger, Angelika Bonauer, Werner Seeger, Andreas M Zeiher, Stefanie Dimmeler, Ralph T Schermuly

  American journal of respiratory and critical care medicine. 12/2011; 185(4):409-19.

  Rationale: MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that theRationale: MicroRNAs (miRs) control various cellular processes in tissue homeostasis and disease by regulating gene expression on the posttranscriptional level. Recently, it was demonstrated that the expression of miR-21 and members of the miR-17-92 cluster was significantly altered in experimental pulmonary hypertension (PH). Objectives: To evaluate the therapeutic efficacy and antiremodeling potential of miR inhibitors in the pathogenesis of PH. Methods: We first tested the effects of miR inhibitors (antagomirs), which were specifically designed to block miR-17 (A-17), miR-21 (A-21), and miR-92a (A-92a) in chronic hypoxia-induced PH in mice and A-17 in monocrotaline-induced PH in rats. Moreover, biological function of miR-17 was analyzed in cultured pulmonary artery smooth muscle cells. Measurements and Main Results: In the PH mouse model, A-17 and A-21 reduced right ventricular systolic pressure, and all antagomirs decreased pulmonary arterial muscularization. However, only A-17 reduced hypoxia-induced right ventricular hypertrophy and improved pulmonary artery acceleration time. In the monocrotaline-induced PH rat model, A-17 treatment significantly decreased right ventricular systolic pressure and total pulmonary vascular resistance index, increased pulmonary artery acceleration time, normalized cardiac output, and decreased pulmonary vascular remodeling. Among the tested miR-17 targets, the cyclin-dependent kinase inhibitor 1A (p21) was up-regulated in lungs undergoing A-17 treatment. Likewise, in human pulmonary artery smooth muscle cells, A-17 increased p21. Overexpression of miR-17 significantly reduced p21 expression and increased proliferation of smooth muscle cells. Conclusions: Our data demonstrate that A-17 improves heart and lung function in experimental PH by interfering with lung vascular and right ventricular remodeling. The beneficial effects may be related to the up-regulation of p21. Thus, inhibition of miR-17 may represent a novel therapeutic concept to ameliorate disease state in PH.

• Early remodeling processes as predictors of diastolic function 5 years after reperfused acute myocardial infarction and intracoronary progenitor cell application.

  Authors: Ulrich Fischer-Rasokat, Jörg Honold, Florian H Seeger, Stephan Fichtlscherer, Volker Schächinger, Stefanie Dimmeler, Andreas M Zeiher, Birgit Assmus

  Clinical research in cardiology : official journal of the German Cardiac Society. 11/2011; 101(3):209-16.

  Ischemia-induced left ventricular (LV) diastolic dysfunction (DD) is increasingly recognized as a therapeutic challenge. While DD during acute myocardial infarction (AMI) determines patients'Ischemia-induced left ventricular (LV) diastolic dysfunction (DD) is increasingly recognized as a therapeutic challenge. While DD during acute myocardial infarction (AMI) determines patients' prognosis, it is unknown how LV remodeling after AMI affects the development of DD. Therefore, we aimed to identify AMI characteristics, which determine diastolic function after 5 years. 41 patients with reperfused AMI and intracoronary infusion of progenitor cells were included into the present analysis of the TOPCARE-AMI trial. At 5-year follow-up, we determined LV diastolic function including LV-filling index (E/E') by echocardiography. Diastolic function was normal in 21 patients (DD class 0), impaired in 14 patients (DD class 1) and pseudonormal in 6 patients (DD class 2). E/E' increased from DD class 0 to 2 (6.6 ± 1.3 vs. 9.0 ± 2.4 vs. 12.1 ± 6.2; p < 0.01). E/E' correlated with the maximal creatine kinase activity during AMI (CKMB(max) r = 0.73, p < 0.01), the change in end-diastolic or end-systolic LV volumes between AMI and 4 months (∆LVEDV r = 0.67, p < 0.01; ∆LVESV r = 0.58, p < 0.01), ejection fraction at 5 years (r = -0.47, p < 0.01) and NT-proBNP serum levels at 5 years (r = 0.37, p < 0.05). Multivariate analysis revealed CKMB(max) (β = 0.56, p < 0.01) and ∆LVEDV (β = 0.38, p < 0.01) as independent predictors for E/E' 5 years after AMI. Adverse early remodeling processes (reflected by LV dilatation between infarction and 4 months) determine long-term diastolic function in patients after reperfused AMI and progenitor cell therapy.

• Epigenetic regulation of endothelial lineage committed genes in pro-angiogenic hematopoietic and endothelial progenitor cells.

  Authors: Kisho Ohtani, Georgios J Vlachojannis, Masamichi Koyanagi, Jes-Niels Boeckel, Carmen Urbich, Ruxandra Farcas, Halvard Bonig, Victor E Marquez, Andreas M Zeiher, Stefanie Dimmeler

  Circulation research. 11/2011; 109(11):1219-29.

  Proangiogenic hematopoietic and endothelial progenitor cells (EPCs) contribute to postnatal neovascularization, but the mechanisms regulating differentiation to the endothelial lineage areProangiogenic hematopoietic and endothelial progenitor cells (EPCs) contribute to postnatal neovascularization, but the mechanisms regulating differentiation to the endothelial lineage are unclear. To elucidate the epigenetic control of endothelial gene expression in proangiogenic cells and EPCs. Here we demonstrate that the endothelial nitric oxide synthase (eNOS) promoter is epigenetically silenced in proangiogenic cells (early EPCs), CD34(+) cells, and mesoangioblasts by DNA methylation and prominent repressive histone H3K27me3 marks. In order to reverse epigenetic silencing to facilitate endothelial commitment, we used 3-deazaneplanocin A, which inhibits the histone methyltransferase enhancer of zest homolog 2 and, thereby, reduces H3K27me3. 3-Deazaneplanocin A was not sufficient to increase eNOS expression, but the combination of 3-deazaneplanocin A and the histone deacetylase inhibitor Trichostatin A augmented eNOS expression, indicating that the concomitant inhibition of silencing histone modification and enhancement of activating histone modification facilitates eNOS expression. In ischemic tissue, hypoxia plays a role in recruiting progenitor cells. Therefore, we examined the effect of hypoxia on epigenetic modifications. Hypoxia modulated the balance of repressive to active histone marks and increased eNOS mRNA expression. The reduction of repressive H3K27me3 was associated with an increase of the histone demethylase Jmjd3. Silencing of Jmjd3 induced apoptosis and senescence in proangiogenic cells and inhibited hypoxia-mediated up-regulation of eNOS expression in mesoangioblasts. These findings provide evidence that histone modifications epigenetically control the eNOS promoter in proangiogenic cells.

• Circulating microRNAs: biomarkers or mediators of cardiovascular diseases?

  Authors: Stephan Fichtlscherer, Andreas M Zeiher, Stefanie Dimmeler

  Arteriosclerosis, thrombosis, and vascular biology. 11/2011; 31(11):2383-90.

  MicroRNAs (miRs) are small, noncoding RNAs that posttranscriptionally control gene expression by inhibiting protein translation or inducing target mRNA destabilization. Besides their intracellularMicroRNAs (miRs) are small, noncoding RNAs that posttranscriptionally control gene expression by inhibiting protein translation or inducing target mRNA destabilization. Besides their intracellular function, recent studies demonstrate that miRs can be exported or released by cells and circulate with the blood in a remarkably stable form. The discovery of circulating miRs opens up intriguing possibilities to use the circulating miR patterns as biomarker for cardiovascular diseases. Cardiac injury as it occurs after acute myocardial infarction increases the circulating levels of several myocardial-derived miRs (eg, miR-1, miR-133, miR-499, miR-208), whereas patients with coronary artery disease or diabetes showed reduced levels of endothelial-enriched miRs, such as miR-126. This review article summarizes the current clinical and experimental studies addressing the role of circulating miRs as a diagnostic or prognostic biomarker in cardiovascular disease. In addition, the mechanisms by which miRs are released and their putative function as long-distance communicators are discussed.

• Transcoronary concentration gradients of circulating microRNAs.

  Authors: Salvatore De Rosa, Stephan Fichtlscherer, Ralf Lehmann, Birgit Assmus, Stefanie Dimmeler, Andreas M Zeiher

  Circulation. 11/2011; 124(18):1936-44.

  Circulating levels of microRNA (miR) have been proposed as biomarkers for cardiovascular disease. To identify the heart as a potential source for miRs released into the circulation, we measuredCirculating levels of microRNA (miR) have been proposed as biomarkers for cardiovascular disease. To identify the heart as a potential source for miRs released into the circulation, we measured concentration gradients across the coronary circulation for muscle-enriched (miR-133a, miR-499, miR-208a), vascular (miR-126, miR-92a), leukocyte-related (miR-155), and platelet-enriched (miR-223) miRs. Circulating miRs were measured by TaqMan polymerase chain reaction in EDTA-plasma simultaneously obtained from the aorta and the coronary venous sinus in patients without coronary artery disease (n=7), with stable coronary artery disease (n=31), and with troponin-positive acute coronary syndromes (n=19). Circulating levels of the muscle-enriched miR-499 (>20-fold; P<0.01), miR-133a (11-fold; P<0.01), and miR-208a (5-fold; P<0.01) were significantly elevated in the aorta of troponin-positive acute coronary syndrome patients compared with patients with coronary artery disease. Importantly, there was a significant increase in circulating levels of miR-499 and miR-133a across the coronary circulation in troponin-positive acute coronary syndrome patients, suggestive of a release into the coronary circulation during myocardial injury. Indeed, miR-499 concentration gradients were significantly correlated with the extent of myocardial damage as measured by high-sensitivity troponin T (r=0.70, P<0.01). In contrast, circulating levels of miR-126 (P=0.16) decreased during transcoronary passage in patients with evidence of myocardial injury, suggesting consumption during transcoronary passage. Muscle-enriched miR-499 and miR-133a are released from the heart into the coronary circulation on myocardial injury, whereas the vascular miR-126 is consumed during transcoronary passage. The differential regulation of circulating miRs during the transcoronary passage might provide important insights to exploit their role as cardiac biomarkers. Clinical Trial Registration- URL: http://www.germanctr.de. Unique identifier: DRKS00000207; in German Clinical Trials Registry.

• Stem cells review series: an introduction.

  Authors: Stefanie Dimmeler, Douglas Losordo

  Circulation research. 09/2011; 109(8):907-9.

• MicroRNA-29 in aortic dilation: implications for aneurysm formation.

  Authors: Reinier A Boon, Timon Seeger, Susanne Heydt, Ariane Fischer, Eduard Hergenreider, Anton J G Horrevoets, Manlio Vinciguerra, Nadia Rosenthal, Sergio Sciacca, Michele Pilato, Paula van Heijningen, Jeroen Essers, Ralf P Brandes, Andreas M Zeiher, Stefanie Dimmeler

  Circulation research. 09/2011; 109(10):1115-9.

  Aging represents a major risk factor for coronary artery disease and aortic aneurysm formation. MicroRNAs (miRs) have emerged as key regulators of biological processes, but their role inAging represents a major risk factor for coronary artery disease and aortic aneurysm formation. MicroRNAs (miRs) have emerged as key regulators of biological processes, but their role in age-associated vascular pathologies is unknown. We aim to identify miRs in the vasculature that are regulated by age and play a role in age-induced vascular pathologies. Expression profiling of aortic tissue of young versus old mice identified several age-associated miRs. Among the significantly regulated miRs, the increased expression of miR-29 family members was associated with a profound downregulation of numerous extracellular matrix (ECM) components in aortas of aged mice, suggesting that this miR family contributes to ECM loss, thereby sensitizing the aorta for aneurysm formation. Indeed, miR-29 expression was significantly induced in 2 experimental models for aortic dilation: angiotensin II-treated aged mice and genetically induced aneurysms in Fibulin-4(R/R) mice. More importantly, miR-29b levels were profoundly increased in biopsies of human thoracic aneurysms, obtained from patients with either bicuspid (n=79) or tricuspid aortic valves (n=30). Finally, LNA-modified antisense oligonucleotide-mediated silencing of miR-29 induced ECM expression and inhibited angiotensin II-induced dilation of the aorta in mice. In conclusion, miR-29-mediated downregulation of ECM proteins may sensitize the aorta to the formation of aneurysms in advanced age. Inhibition of miR-29 in vivo abrogates aortic dilation in mice, suggesting that miR-29 may represent a novel molecular target to augment matrix synthesis and maintain vascular wall structural integrity.

• Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin.

  Authors: David Kaluza, Jens Kroll, Sabine Gesierich, Tso-Pang Yao, Reinier A Boon, Eduard Hergenreider, Marc Tjwa, Lothar Rössig, Edward Seto, Hellmut G Augustin, Andreas M Zeiher, Stefanie Dimmeler, Carmen Urbich

  The EMBO journal. 08/2011; 30(20):4142-56.

  Histone deacetylases (HDACs) deacetylate histones and non-histone proteins, thereby affecting protein activity and gene expression. The regulation and function of the cytoplasmic class IIb HDAC6 inHistone deacetylases (HDACs) deacetylate histones and non-histone proteins, thereby affecting protein activity and gene expression. The regulation and function of the cytoplasmic class IIb HDAC6 in endothelial cells (ECs) is largely unexplored. Here, we demonstrate that HDAC6 is upregulated by hypoxia and is essential for angiogenesis. Silencing of HDAC6 in ECs decreases sprouting and migration in vitro and formation of functional vascular networks in matrigel plugs in vivo. HDAC6 regulates zebrafish vessel formation, and HDAC6-deficient mice showed a reduced formation of perfused vessels in matrigel plugs. Consistently, overexpression of wild-type HDAC6 increases sprouting from spheroids. HDAC6 function requires the catalytic activity but is independent of ubiquitin binding and deacetylation of α-tubulin. Instead, we found that HDAC6 interacts with and deacetylates the actin-remodelling protein cortactin in ECs, which is essential for zebrafish vessel formation and which mediates the angiogenic effect of HDAC6. In summary, we show that HDAC6 is necessary for angiogenesis in vivo and in vitro, involving the interaction and deacetylation of cortactin that regulates EC migration and sprouting.

• Homing of progenitor cells to ischemic tissues.

  Authors: Emmanouil Chavakis, Stefanie Dimmeler

  Antioxidants & redox signaling. 08/2011; 15(4):967-80.

  Progenitor cells mobilized from the bone marrow are recruited to ischemic tissues and increase neovascularization. Cell therapy is a promising new therapeutic option for treating patients withProgenitor cells mobilized from the bone marrow are recruited to ischemic tissues and increase neovascularization. Cell therapy is a promising new therapeutic option for treating patients with ischemic disorders. The efficiency of cell therapy to augment recovery after ischemia depends on the sufficient recruitment and engraftment of the cells to the target tissue. Homing to sites of active neovascularization is a complex process depending on a timely and spatially orchestrated interplay between chemokines, chemokine receptors, adhesion molecules (selectins and integrins), and intracellular signaling cascades, including also oxidative signaling. This review will focus on the homing mechanisms of progenitor and stem cells to ischemic tissues. Specifically, we discuss the role of chemokines and adhesion molecules such as selectins and integrins and the crosstalk between chemokines and integrins in progenitor cell homing.

• Maladaptive hypertrophy after acute myocardial infarction positive effect of bone marrow-derived stem cell therapy on regional remodeling measured by cardiac MRI.

  Authors: Andreas Rolf, Birgit Assmus, Volker Schächinger, Johannes Rixe, Susanne Möllmann, Helge Möllmann, Stefanie Dimmeler, Andreas M Zeiher, Christian W Hamm, Thorsten Dill

  Clinical research in cardiology : official journal of the German Cardiac Society. 06/2011; 100(11):983-92.

  In the aftermath of myocardial infarction, increased loading conditions will trigger hypertrophy of viable myocardium. This in turn causes deterioration of regional contractility. Cardiac magneticIn the aftermath of myocardial infarction, increased loading conditions will trigger hypertrophy of viable myocardium. This in turn causes deterioration of regional contractility. Cardiac magnetic resonance imaging (cMRI) allows the exact differentiation of viable and infarcted myocardium and therefore the measurement of regional wall thickness and function. Bone marrow-derived stem cell (BMC) transfer has been shown to improve global function and remodeling. The present study examines the effect of BMC transfer on regional remodeling and function after myocardial infarction by cMRI. Fifty-four patients of the MR substudy of the REPAIR-AMI trial have been studied at baseline and 12-month follow-up. Enddiastolic wall thickness (EDWT) and wall thickening (WT%) have been measured on SSFP cine sequences. Enddiastolic wall thickness decreased in both placebo and BMC groups in viable as well as infarcted segments. The effect was largest in the pre-specified subgroup of patients below the median EF of 48.9% (infarcted segments -1.14 mm Placebo vs. -1.91 mm BMC, p for interaction 0.01, remote segments -0.19 mm Placebo vs. -0.94 mm BMC, p for interaction 0.00001). Corrected for baseline values BMC therapy yielded smaller EDWT at 12 months in infarcted and remote segments (infarcted 7.58 mm Placebo vs. 6.13 mm BMC p = 0.0001, remote 8.76 mm Placebo vs. 7.32 mm BMC, p = 0.0001). This was associated with better contractility within the infarcted segments among BMC patients (WT% 24.17% Placebo vs. 49.31% BMC, p = 0.0001). The WT% was inversely correlated with EDWT (r = -0.37, p = 0.0001). Bone marrow-derived stem cell therapy yields smaller EDWT when compared with placebo patients suggesting a positive effect on maladaptive hypertrophy of viable myocardium. This notion is supported by the enhanced regional contractility within the BMC group which is inversely correlated with EDWT.