Franz Hofmann

Technische Universität München, München, Bavaria, Germany

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Publications (445)2642.65 Total impact

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    ABSTRACT: The voltage-gated Ca(2+) (CaV) channel acts as a key player in β cell physiology and pathophysiology. β cell CaV channels undergo hyperactivation subsequent to exposure to type 1 diabetic (T1D) serum resulting in increased cytosolic free Ca(2+) concentration and thereby Ca(2+)-triggered β cell apoptosis. The present study was aimed at revealing the subtypes of CaV1 channels hyperactivated by T1D serum as well as the biophysical mechanisms responsible for T1D serum-induced hyperactivation of β cell CaV1 channels. Patch-clamp recordings and single-cell RT-PCR analysis were performed in pancreatic β cells from CaV1 channel knockout and corresponding control mice. We now show that functional CaV1.3 channels are expressed in a subgroup of islet β cells from CaV1.2 knockout mice (CaV1.2(-/-)). T1D serum enhanced whole-cell CaV currents in islet β cells from CaV1.3 knockout mice (CaV1.3(-/-)). T1D serum increased the open probability and number of functional unitary CaV1 channels in CaV1.2(-/-) and CaV1.3(-/-) β cells. These data demonstrate that T1D serum hyperactivates both CaV1.2 and CaV1.3 channels by increasing their conductivity and number. These findings suggest CaV1.2 and CaV1.3 channels as potential targets for anti-diabetes therapy.
    Cellular and Molecular Life Sciences CMLS 10/2014; · 5.62 Impact Factor
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    ABSTRACT: The presence of cGMP-dependent protein kinase I (cGKI) in murine adipocytes has been questioned, although cGKI was implicated in the thermogenic program of fat cells (FCs) and to exert anti-hypertrophic/-inflammatory effects in white adipose tissue. Herein, cGKI was detected in adipocytes from control mice, whereas FCs from global cGKI knockouts (cGKI(-/-)) and cGKIα rescue (αRM) mice remained cGKI-negative. cGKI mutants exhibit decreased adipocyte size, plasma leptin levels and reduced body-weights as compared to litter-matched controls. Low abundance of adiponectin in WAT and plasma of αRM animals together with previously confirmed high IL-6 levels indicate a low-grade inflammation. However, αRMs were protected from streptozotocin-induced hyperglycemia. Our results suggest that cGMP/cGKI affects both glucose and FC homeostasis in more complex mode than previously thought.
    Biochemical and Biophysical Research Communications 08/2014; · 2.28 Impact Factor
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    ABSTRACT: Conflicting results have been reported for the roles of cGMP and cGMP-dependent protein kinase I (cGKI) in various pathological conditions leading to cardiac hypertrophy and fibrosis. A cardioprotective effect of cGMP/cGKI has been reported in whole animals and isolated cardiomyocytes, but recent evidence from a mouse model expressing cGKIβ only in smooth muscle (βRM) but not in cardiomyocytes, endothelial cells, or fibroblasts has forced a reevaluation of the requirement for cGKI activity in the cardiomyocyte antihypertrophic effects of cGMP. In particular, βRM mice developed the same hypertrophy as WT controls when subjected to thoracic aortic constriction or isoproterenol infusion. Here, we challenged βRM and WT (Ctr) littermate control mice with angiotensin II (AII) infusion (7 d; 2 mg⋅kg(-1)⋅d(-1)) to induce hypertrophy. Both genotypes developed cardiac hypertrophy, which was more pronounced in Ctr animals. Cardiomyocyte size and interstitial fibrosis were increased equally in both genotypes. Addition of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, in the drinking water had a small effect in reducing myocyte hypertrophy in WT mice and no effect in βRM mice. However, sildenafil substantially blocked the increase in collagen I, fibronectin 1, TGFβ, and CTGF mRNA in Ctr but not in βRM hearts. These data indicate that, for the initial phase of AII-induced cardiac hypertrophy, lack of cardiomyocyte cGKI activity does not worsen hypertrophic growth. However, expression of cGKI in one or more cell types other than smooth muscle is necessary to allow the antifibrotic effect of sildenafil.
    Proceedings of the National Academy of Sciences 08/2014; · 9.81 Impact Factor
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    ABSTRACT: Mouse pancreatic β- and α-cells are equipped with voltage-gated Na+ currents that inactivate over widely different membrane potentials (half-maximal inactivation [V0.5] at -100 mV and -50 mV in β- and α-cells, respectively). Single-cell PCR analyses show that both α- and β-cells have Nav1.3 (Scn3) and Nav1.7 (Scn9a) α-subunits, but their relative proportions differ: β-cells principally express Nav1.7 and α-cells Nav1.3. In α-cells, genetically ablating Scn3a reduces the Na+ current by 80%. In β-cells, knockout of Scn9a lowers the Na+ current by >85%, unveiling a small Scn3a-dependent component. Glucagon and insulin secretion are inhibited in Scn3a−/− islets but unaffected in Scn9a-deficient islets. Thus Nav1.3 is the functionally important Na+ channel α-subunit in both α- and β-cells because Nav1.7 is largely inactive at physiological membrane potentials due to its unusually negative voltage dependence of inactivation. Interestingly, the Nav1.7 sequence in brain and islets is identical and yet the V0.5 for inactivation is >30mV more negative in β-cells. This may indicate the presence of an intracellular factor that modulates the voltage dependence of inactivation.This article is protected by copyright. All rights reserved
    The Journal of Physiology 08/2014; · 4.38 Impact Factor
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    ABSTRACT: Within the suprachiasmatic nucleus (SCN) of the hypothalamus, circadian timekeeping and resetting have been shown to be largely dependent on both membrane depolarization and intracellular second-messenger signaling. In both of these processes, voltage-gated calcium channels (VGCCs) mediate voltage-dependent calcium influx, which propagates neural impulses by stimulating vesicle fusion and instigates intracellular pathways resulting in clock gene expression. Through the cumulative actions of these processes, the phase of the internal clock is modified to match the light cycle of the external environment. To parse out the distinct roles of the L-type VGCCs, we analyzed mice deficient in Cav1.2 (Cacna1c) in brain tissue. We found that mice deficient in the Cav1.2 channel exhibited a significant reduction in their ability to phase-advance circadian behavior when subjected to a light pulse in the late night. Furthermore, the study revealed that the expression of Cav1.2 mRNA was rhythmic (peaking during the late night) and was regulated by the circadian clock component REV-ERBα. Finally, the induction of clock genes in both the early and late subjective night was affected by the loss of Cav1.2, with reductions in Per2 and Per1 in the early and late night, respectively. In sum, these results reveal a role of the L-type VGCC Cav1.2 in mediating both clock gene expression and phase advances in response to a light pulse in the late night.
    Journal of Biological Rhythms 08/2014; 29(4):288-98. · 3.23 Impact Factor
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    ABSTRACT: cGMP inhibits hypertrophy, decreases fibrosis, and protects against cardiac ischemia-reperfusion (I/R) injury. Gene-targeting studies have not defined a clear role for its major downstream effector, cGMP-dependent protein kinase I (cGKI), in cardiac hypertrophy, but do implicate cGMP-cGKI signaling in fibrosis and I/R injury. No direct cGKI activators have advanced to clinical trials, whereas cardiac trials of agents that modulate cGMP via particulate or soluble guanylyl cyclases (GCs) and phosphodiesterase 5 (PDE5) are ongoing. Here we review concerns arising from preclinical and clinical studies that question whether targeting the cGMP pathway remains an encouraging concept for management of heart dysfunction. So far, trial results for GC modulators are inconclusive, and sildenafil, a PDE5 inhibitor, although cardioprotective in mouse models, has not shown positive clinical results. Preclinical cardioprotection observed for sildenafil may result from inhibition of PDE5 in non-cardiomyocytes or off-target effects, possibly on PDE1C. On the basis of such mechanistic considerations, re-evaluation of the cellular localization of drug target(s) and intervention protocols for cGMP-elevating agents may be needed.
    Trends in Pharmacological Sciences 06/2014; · 9.25 Impact Factor
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    ABSTRACT: Atrial natriuretic peptide (ANP)/cGMPs cause diuresis and natriuresis. Their downstream effectors beyond cGMP remain unclear. To elucidate a probable function of cGMP-dependent protein kinase II (cGKII), we investigated renal parameters in different conditions (basal, salt diets, starving, water load) using a genetically modified mouse model (cGKII-KO), but did not detect any striking differences between WT and cGKII-KO. Thus, cGKII is proposed to play only a marginal role in the adjustment of renal concentration ability to varying salt loads without water restriction or starving conditions. When WT mice were subjected to a volume load (performed by application of a 10-mM glucose solution (3 % of BW) via feeding needle), they exhibited a potent diuresis. In contrast, urine volume was decreased significantly in cGKII-KO. We showed that AQP2 plasma membrane (PM) abundance was reduced for about 50 % in WT upon volume load, therefore, this might be a main cause for the enhanced diuresis. In contrast, cGKII-KO mice almost completely failed to decrease AQP2-PM distribution. This significant difference between both genotypes is not induced by an altered p-Ser256-AQP2 phosphorylation, as phosphorylation at this site decreases similarly in WT and KO. Furthermore, sodium excretion was lowered in cGKII-KO mice during volume load. In summary, cGKII is only involved to a minor extent in the regulation of basal renal concentration ability. By contrast, cGKII-KO mice are not able to handle an acute volume load. Our results suggest that membrane insertion of AQP2 is inhibited by cGMP/cGKII.
    Pflügers Archiv - European Journal of Physiology 01/2014; · 4.87 Impact Factor
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    ABSTRACT: The L-type Cav1.2 calcium channel is present throughout the animal kingdom and is essential for some aspects of CNS function, cardiac and smooth muscle contractility, neuroendocrine regulation, and multiple other processes. The L-type CaV1.2 channel is built by up to four subunits; all subunits exist in various splice variants that potentially affect the biophysical and biological functions of the channel. Many of the CaV1.2 channel properties have been analyzed in heterologous expression systems including regulation of the L-type CaV1.2 channel by Ca(2+) itself and protein kinases. However, targeted mutations of the calcium channel genes confirmed only some of these in vitro findings. Substitution of the respective serines by alanine showed that β-adrenergic upregulation of the cardiac CaV1.2 channel did not depend on the phosphorylation of the in vitro specified amino acids. Moreover, well-established in vitro phosphorylation sites of the CaVβ2 subunit of the cardiac L-type CaV1.2 channel were found to be irrelevant for the in vivo regulation of the channel. However, the molecular basis of some kinetic properties, such as Ca(2+)-dependent inactivation and facilitation, has been approved by in vivo mutagenesis of the CaV1.2α1 gene. This article summarizes recent findings on the in vivo relevance of well-established in vitro results.
    Physiological Reviews 01/2014; 94(1):303-26. · 30.17 Impact Factor
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    ABSTRACT: α1-Adrenergic stimulation increases blood vessel tone in mammals. This process involves a number of intracellular signaling pathways that include signaling via phospholipase C, diacylglycerol (DAG), and protein kinase C. So far, it is not certain whether signaling via phospholipase D (PLD) and PLD-derived DAG is involved in this process. We asked whether PLD participates in the α1-adrenergic-mediated signaling in vascular smooth muscle. α1-Adrenergic-induced contraction was assessed by myography of isolated aortic rings and by pressure recordings using the hindlimb perfusion model in mice. The effects of the PLD inhibitor 1-butanol (IC50 0.15 vol%) and the inactive congener 2-butanol were comparatively studied. Inhibition of PLD by 1-butanol reduced specifically the α1-adrenergic-induced contraction and the α1-adrenergic-induced pressure increase by 10 and 40% of the maximum, respectively. 1-Butanol did not influence the aortic contractions induced by high extracellular potassium, by the thromboxane analog U46619, or by a phorbol ester. The effects of 1-butanol were absent in mice that lack PLD1 (Pld1(-/-) mice) or that selectively lack the CaV1.2 channel in smooth muscle (sm-CaV1.2(-/-) mice) but still present in the heterozygous control mice. α1-Adrenergic contraction of vascular smooth muscle involves activation of PLD1, which controls a portion of the α1-adrenergic-induced CaV1.2 channel activity.-Wegener, J. W., Loga, F, Stegner, D., Nieswandt, B., Hofmann, F. Phospholipase D1 is involved in α1-adrenergic contraction of murine vascular smooth muscle.
    The FASEB Journal 11/2013; · 5.70 Impact Factor
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    ABSTRACT: Purpose: α1-adrenergic stimulation increases blood vessel tone in mammals. This process involves a number of intracellular signaling pathways which include signaling via phospholipase C (PLC), diacylglycerol (DAG), and protein kinase C (PKC). So far, it is uncertain whether signaling via phospholipase D (PLD) and PLD-derived DAG is involved in this process. We asked whether PLD participates in the α1-adrenergic-mediated signaling in vascular smooth muscle. Procedures: α1-adrenergic-induced contraction was assessed by myography of isolated aortic rings and by pressure recordings using the hind limb perfusion model in mice. The effects of the PLD inhibitor 1-butanol (IC50 0.15 Vol%) and the inactive congener 2-butanol were comparatively studied. Findings: Inhibition of PLD by 1-butanol reduced specifically α1-adrenergic-induced contraction and α1-adrenergic-induced pressure increase by 10% and 40% of the maximum, respectively. 1-butanol did not influence aortic contractions induced by high extracellular potassium, by the thromboxane analogue U46619, or by a phorbol ester. The effects of 1-butanol were absent in mice that lack PLD1 (Pld1-/- mice) or that selectively lack CaV1.2 channel in smooth muscle (sm-CaV1.2-/- mice) but still present in the heterozygous control mice. Conclusions: α1-adrenergic contraction of vascular smooth muscle involves activation of PLD1 which controls a portion of α1-adrenergic-induced CaV1.2 channel activity.
    The FASEB Journal 11/2013; · 5.70 Impact Factor
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    ABSTRACT: Signaling via cGMP-dependent protein kinase I (cGKI) is the major pathway in vascular smooth muscle (SM), by which endothelial NO regulates vascular tone. Recent evidence suggests that canonical transient receptor potential (Trpc) channels are targets of cGKI in SM and mediate the relaxant effects of cGMP signaling. We tested this concept by investigating the role of cGMP/cGKI signaling on vascular tone and peripheral resistance using Trpc6(-/-), Trpc3(-/-), Trpc3(-/-)/6(-/-), Trpc1(-/-)/3(-/-)/6(-/-), and SM-specific cGKI(-/-) (sm-cGKI(-/-)) mice.Methods and Resultsα-adrenergic stimulation induced similar contractions in L-NAME-treated aorta and comparably increased peripheral pressure in hind limbs from all mouse lines investigated. After α-adrenergic stimulation, 8-Br-cGMP diminished similarly aortic tone and peripheral pressure in control, Trpc6(-/-), Trpc3(-/-), Trpc3(-/-)/6(-/-), and Trpc1(-/-)/3(-/-)/6(-/-) mice but not in sm-cGKI(-/-) mice. In untreated aorta, α-adrenergic stimulation induced similar contractions in aorta from control and Trpc3(-/-) mice but larger contractions in sm-cGKI(-/-), Trpc6(-/-), Trpc3(-/-)/6(-/-), and Trpc1(-/-)/3(-/-)/6(-/-) mice indicating a functional link between cGKI and Trpc6 channels. Trpc3 channels were detected by immunocytochemistry in both isolated aortic SM cells (SMC) and aortic endothelial cells (EC), whereas Trpc6 channels were detected only in EC. Phenylephrine-stimulated Ca(2+) levels were similar in SMC from Ctr and Trpc6(-/-) mice. Carbachol-stimulated Ca(2+) levels were reduced in EC from Trpc6(-/-) mice. Stimulated Ca(2+) levels were lowered by 8-Br-cGMP in Ctr but not in Trpc6(-/-) EC. The results suggest that cGKI and Trpc1,3,6 channels are not functionally coupled in vascular SM. Deletion of Trpc6 channels impaired endothelial cGKI signaling and vasodilator tone in aorta.
    Cardiovascular Research 07/2013; · 5.81 Impact Factor
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    ABSTRACT: Histamine increases microvascular endothelial leakage by activation of complex calcium-dependent and -independent signaling pathways. Atrial natriuretic peptide (ANP) via its cGMP-forming guanylyl cyclase-A (GC-A) receptor counteracts this response. Here, we characterized the molecular mechanisms underlying this interaction, especially the role of cGMP-dependent protein kinase I (cGKI). We combined intravital microscopy studies of the mouse cremaster microcirculation with experiments in cultured microvascular human dermal endothelial cells. In wild-type mice, ANP had no direct effect on the extravasation of fluorescent dextran from postcapillary venules, but strongly reduced the histamine-provoked vascular leakage. This anti-inflammatory effect of ANP was abolished in mice with endothelial-restricted inactivation of GC-A or cGKI. Histamine-induced increases in endothelial [Ca(2+)]i in vitro and of vascular leakage in vivo were markedly attenuated by the Ca(2+)-entry inhibitor SKF96365 and in mice with ablated transient receptor potential canonical (TRPC) 6 channels. Conversely, direct activation of TRPC6 with hyperforin replicated the hyperpermeability responses to histamine. ANP, via cGKI, stimulated the inhibitory phosphorylation of TRPC6 at position Thr69 and prevented the hyperpermeability responses to hyperforin. Moreover, inhibition of cGMP degradation by the phosphodiesterase 5 inhibitor sildenafil prevented the edematic actions of histamine in wild types but not in mice with endothelial GC-A or cGKI deletion. ANP attenuates the inflammatory actions of histamine via endothelial GC-A/cGMP/cGKI signaling and inhibitory phosphorylation of TRPC6 channels. The therapeutic potential of this novel regulatory pathway is indicated by the observation that sildenafil improves systemic endothelial barrier functions by enhancing the endothelial effects of endogenous ANP.
    Arteriosclerosis Thrombosis and Vascular Biology 06/2013; · 6.34 Impact Factor
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    ABSTRACT: The purpose of this study was to investigate the influence of cGMP-dependent kinase I (cGKI) on platelet production. We used hematology analyser to measure platelet counts in conventional cGKI-null mutants (cGKI(L1/L1)), gene-targeted cGKIα/β rescue mice (referred to as cGKI-smooth muscle [SM]) in which cGKI expression is specifically restored only in SM, platelet factor 4-Cre(tg/+); cGKI(L2/L2) mice in which the cGKI protein was specifically deleted in the megakaryocyte/platelet lineage and cGKI-deficient bone marrow-chimeras. Thrombocytosis was detected in cGKI(L1/L1) and in cGKI-SM. In contrast, neither platelet factor 4-Cre(tg/+); cGKI(L2/L2) nor cGKI-deficient bone marrow-chimeras displayed a thrombocytosis phenotype, indicating that the high platelet count in cGKI(L1/L1) and cGKI-SM mutants is attributable to loss of an extrinsic signal rather than reflecting an intrinsic defect in megakaryopoiesis. Cytometric analyses further showed that stimulation of bone marrow-derived wild-type megakaryocytes in vitro using serum preparations obtained from cGKI-SM mutants strongly accelerated megakaryopoiesis, suggesting that the high platelet count develops in response to serum factors. Indeed, using ELISA assay, we found elevated levels of interleukin-6, a known stimulator of thrombopoiesis, in cGKI-SM mutant serum, whereas interleukin-6 levels were unaltered in platelet factor 4-Cre(tg/+); cGKI(L2/L2) mice and cGKI-deficient bone marrow-chimeras. Accordingly, antibody-mediated blockade of interleukin-6 normalized platelet counts in cGKI-SM mice. Abnormal cGMP/cGKI signaling in nonhematopoietic cells affects thrombopoiesis via elevated interleukin-6 production and results in thrombocytosis in vivo. Dysfunction of cGMP/cGKI signaling in nonhematopoietic cells contributes to a high platelet count, which is potentially associated with thrombosis.
    Arteriosclerosis Thrombosis and Vascular Biology 06/2013; · 6.34 Impact Factor
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    ABSTRACT: Cyclic guanosine monophosphate (cGMP) is synthesized by nitric oxide or natriuretic peptide-stimulated guanylyl cyclases and exhibits pleiotropic regulatory functions in the kidney. Hence, integration of cGMP signaling by cGMP-dependent protein kinases (cGKs) might play a critical role in renal physiology; however, detailed renal localization of cGKs is still lacking. Here, we performed an immunohistochemical analysis of cGKIα and cGKIβ isozymes in the mouse kidney and found both in arterioles, the mesangium, and within the cortical interstitium. In contrast to cGKIα, the β-isoform was not detected in the juxtaglomerular apparatus or medullary fibroblasts. Since interstitial fibroblasts play a prominent role in interstitial fibrosis, we focused our study on cGKI function in the interstitium, emphasizing a functional differentiation of both isoforms, and determined whether cGKIs influence renal fibrosis induced by unilateral ureter obstruction. Treatment with the guanylyl cyclase activators YC1 or isosorbide dinitrate showed stronger antifibrotic effects in wild-type than in cGKI-knockout or in smooth muscle-cGKIα-rescue mice, which are cGKI deficient in the kidney except in the renal vasculature. Moreover, fibrosis influenced the mRNA and protein expression levels of cGKIα more strongly than cGKIβ. Thus, our results indicate that cGMP, acting primarily through cGKIα, is an important suppressor of kidney fibrosis.Kidney International advance online publication, 12 June 2013; doi:10.1038/ki.2013.219.
    Kidney International 06/2013; · 8.52 Impact Factor
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    ABSTRACT: The enteric nervous system contains excitatory and inhibitory neurons, which control contraction and relaxation of smooth muscle cells as well as gastrointestinal motor activity. Little is known about the exact cellular mechanisms of neuronal signal transduction to smooth muscle cells in the gut. Here we generate a c-Kit(CreERT2) knock-in allele to target a distinct population of pacemaker cells called interstitial cells of Cajal. By genetic loss-of-function studies, we show that interstitial cells of Cajal, which generate spontaneous electrical slow waves and thus rhythmic contractions of the smooth musculature, are essential for transmission of signals from enteric neurons to gastrointestinal smooth muscle cells. Interstitial cells of Cajal, therefore, integrate excitatory and inhibitory neurotransmission with slow-wave activity to orchestrate peristaltic motor activity of the gut. Impairment of the function of interstitial cells of Cajal causes severe gastrointestinal motor disorders. The results of our study show at the genetic level that these disorders are not only due to loss of slow-wave activity but also due to disturbed neurotransmission.
    Nature Communications 03/2013; 4:1630. · 10.74 Impact Factor
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    ABSTRACT: Protein kinase G type I (PKGI) plays a critical role in survival signaling of pre- and postconditioning downstream of cardiac cGMP. However, it is unclear whether PKGI exerts its protective effects in the cardiomyocyte or if other cardiac cell types are involved, and whether nitric oxide (NO) metabolism can target cardiomyocyte mitochondria independently of cGMP/PKGI. We tested whether protection against reperfusion injury by ischemic postconditioning (IPost), soluble guanylyl cyclase (sGC) activation and inhibition, adenosine A(2B) receptor (A(2B)AR) agonist, phosphodiesterase type-5 (PDE-5) inhibitor, or mitochondria-targeted S-nitrosothiol (MitoSNO) was affected by a cardiomyocyte-specific ablation of the PKGI gene in the mouse (CMG-KO). In situ hearts underwent 30 min of regional ischemia followed by 2 h of reperfusion. As expected, in CMG-CTRs all interventions at early reperfusion lead to profound infarct size reduction: IPost (six cycles of 10-s reperfusion and 10-s coronary occlusion) with or without treatment with the sGC inhibitor ODQ, treatment with the specific sGC activator BAY58-2667 (BAY58), the selective A(2B)AR agonist BAY60-6583 (BAY60), PDE-5 inhibitor sildenafil, and MitoSNO. MitoSNO accumulates within mitochondria, driven by the membrane potential, where it generates NO· and S-nitrosates thiol proteins. In contrast, the hearts of CMG-KO animals were not protected by BAY58 and sildenafil, whereas the protective effects of IPost, IPost with ODQ, BAY60, and MitoSNO were unaffected by the lack of PKGI. Taken together, PKGI is important for the protection against ischemia reperfusion injury afforded by sGC activation or PDE-5 inhibition. However, the beneficial effects of IPost, activation of the A(2B)AR, as well as the direct effects via mitochondrial S-nitrosation do not depend on PKGI in cardiomyocytes.
    Archiv für Kreislaufforschung 03/2013; 108(2):337. · 7.35 Impact Factor
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    ABSTRACT: Cardiac Ca(V)1.2 channels play a critical role in cardiac function. It has been proposed that the carboxyl-terminal intracellular tail of the Ca(V)1.2 channel is the target of Ca(2+)-dependent and Ca(2+)-independent regulation of the channel. Recent studies on C-terminal truncated forms of the Ca(V)1.2 channel reported neonatal death, reduced Ca(V)1.2 current, and failure of β-adrenergic stimulation of these channels in ventricular cardiomyocytes (CMs). Here, we used atrial CMs at embryonic day 18.5 that expressed a C-terminal truncated form of the Ca(V)1.2 channel (Stop/Stop). Surprisingly, the atrial CMs showed robust L-type Ca(2+) currents which could be stimulated by forskolin, an activator of adenylyl cyclase. These currents exhibited a left-ward shift in the voltage-dependent activation curve and a reduced sensitivity to the Ca(2+) channel blocker isradipine as compared to currents in wild-type atrial CMs. RT-PCR analysis revealed normal levels of mRNA for the Ca(V)1.2 channel but a twofold increase in the level of mRNA for the Ca(V)1.3 channel in the Stop/Stop atrium as compared to wild-type atrium. A Western blot analysis indicated an increase of Ca(V)1.3 protein in the Stop/Stop atrium. We suggest that, in contrast to Stop/Stop ventricular CMs, Stop/Stop atrial CMs can compensate the functional loss of the truncated Ca(V)1.2 channel with an upregulation of the Ca(V)1.3 channel.
    Pflügers Archiv - European Journal of Physiology 01/2013; · 4.87 Impact Factor
  • Ding J, Domes K, Hofmann F, Wegener JW
    Pflügers Archiv - European Journal of Physiology 01/2013; · 4.87 Impact Factor
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    BMC Pharmacology 01/2013; 11(1).
  • Franz Hofmann, Jörg W Wegener
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    ABSTRACT: cGMP-dependent protein kinases (cGK) are serine/threonine kinases that are widely distributed in eukaryotes. Two genes-prkg1 and prkg2-code for cGKs, namely, cGKI and cGKII. In mammals, two isozymes, cGKIα and cGKIβ, are generated from the prkg1 gene. The cGKI isozymes are prominent in all types of smooth muscle, platelets, and specific neuronal areas such as cerebellar Purkinje cells, hippocampal neurons, and the lateral amygdala. The cGKII prevails in the secretory epithelium of the small intestine, the juxtaglomerular cells, the adrenal cortex, the chondrocytes, and in the nucleus suprachiasmaticus. Both cGKs are major downstream effectors of many, but not all, signalling events of the NO/cGMP and the ANP/cGMP pathways. cGKI relaxes smooth muscle tone and prevents platelet aggregation, whereas cGKII inhibits renin secretion, chloride/water secretion in the small intestine, the resetting of the clock during early night, and endochondral bone growth. This chapter focuses on the involvement of cGKs in cardiovascular and non-cardiovascular processes including cell growth and metabolism.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 1020:17-50. · 1.29 Impact Factor

Publication Stats

18k Citations
2,642.65 Total Impact Points


  • 1991–2014
    • Technische Universität München
      • Institute of Pharmacology and Toxicology
      München, Bavaria, Germany
    • Institut für Pharmakologie und Toxikologie der Bundeswehr
      München, Bavaria, Germany
  • 2010–2013
    • Universität Regensburg
      • Department of Pharmacology and Toxicology
      Regensburg, Bavaria, Germany
  • 2012
    • Hannover Medical School
      • Department of Gastroenterology, Hepatology and Endocrinology
      Hannover, Lower Saxony, Germany
  • 2007–2011
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      Erlangen, Bavaria, Germany
  • 1999–2011
    • Ludwig-Maximilian-University of Munich
      • Department of Pharmacy
      München, Bavaria, Germany
    • CUNY Graduate Center
      New York City, New York, United States
  • 1992–2011
    • Deutsches Herzzentrum München
      München, Bavaria, Germany
  • 2005–2008
    • University of Tuebingen
      • • Interfaculty Institute for Biochemistry
      • • Division of Pharmacology, Clinical Pharmacy and Toxicology
      Tübingen, Baden-Wuerttemberg, Germany
  • 2004–2008
    • Goethe-Universität Frankfurt am Main
      • Institut für Pharmazeutische Biologie
      Frankfurt am Main, Hesse, Germany
  • 2002–2008
    • Slovak Academy of Sciences
      • Institute of Molecular Physiology and Genetics
      Bratislava, Bratislavsky Kraj, Slovakia
    • Johannes Gutenberg-Universität Mainz
      • Department of Pharmacology
      Mainz, Rhineland-Palatinate, Germany
    • University of Leuven
      Louvain, Flanders, Belgium
  • 1994–2007
    • Max-Delbrück-Centrum für Molekulare Medizin
      • Research Team Developmental Neurobiology
      Berlin, Land Berlin, Germany
  • 1986–2005
    • Universität des Saarlandes
      • • Physikalische Chemie
      • • Fachbereich Experimentelle und Klinische Pharmakologie und Toxikologie
      Saarbrücken, Saarland, Germany
  • 2003
    • Université de Fribourg
      • Département de médecine
      Fribourg, FR, Switzerland
  • 2000
    • Universidad Nacional Autónoma de México
      • Department of Cellular Biology
      Mexico City, The Federal District, Mexico
  • 1996–2000
    • Universität Ulm
      Ulm, Baden-Württemberg, Germany
  • 1993
    • University of Rochester
      • School of Medicine and Dentistry
      Rochester, NY, United States
  • 1981–1985
    • Universität Heidelberg
      • Institute of Pharmacology
      Heidelburg, Baden-Württemberg, Germany