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ABSTRACT: Background: Pulmonary artery smooth muscle cell (PASMC) in Pulmonary arterial hypertension (PAH) contribute to the obliterative vascular remodeling and are characterized by enhanced proliferation, suppressed apoptosis and a much less studied increased migration potential. One of the major proteins that regulate cell migration is Focal Adhesion Kinase (FAK), but its role in PAH is incompletely understood. We hypothesized that targeting cell migration by FAK inhibition may be a new therapeutic strategy in PAH.
Methods/Results: In vivo, inhalation of FAK-siRNA (n=5) or oral delivery of PF228 (FAK inhibitor, n=5) inhibited rat monocrotaline (MCT)-induced PAH, improving hemodynamics, vascular remodeling (media thickness) and right ventricular hypertrophy. In vitro, FAK was activated in PAH human lungs (n=8) or PASMC compared to those form healthy subjects (Western Blot, n=5), in a Src-dependent manner, as it was reversed by the specific Src inhibitor PP2. The degree of FAK phosphorylation at Y576 correlated positively with pulmonary vascular resistance in PAH patients. FAK inhibition (siRNA, PF228 and PP2) in PAH-PASMCs induced a 5-fold increase in apoptosis (%TUNEL), a 2.5-fold decrease in proliferation (%Ki67), an 18% decrease in cell migration (colorimetric assay) and a 50% decrease in cell invasion (wound healing).
Conclusion: Suppressing PASMC migration by FAK inhibition inhibits PAH progression and may open a new therapeutic window in PAH.
European Respiratory Journal 05/2013; · 5.89 Impact Factor
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ABSTRACT: Rationale: Mitochondrial signaling regulates both the acute and chronic response of the pulmonary circulation to hypoxia, and suppressed mitochondrial glucose oxidation (GO) contributes to the apoptosis-resistance and proliferative diathesis in the vascular remodeling in pulmonary hypertension (PHT). Hypoxia directly inhibits GO, while endoplasmic reticulum (ER)-stress can indirectly inhibit GO by decreasing mitochondrial calcium (Ca(2+)m levels). Both hypoxia and ER-stress promote proliferative pulmonary vascular remodeling. Uncoupling protein 2 (UCP2) has been shown to conduct calcium from the ER to mitochondria and suppress mitochondrial function. Objective: We hypothesized that UCP2 deficiency reduces Ca(2+)m in pulmonary artery smooth muscle cells (PASMCs), mimicking the effects of hypoxia and ER-stress on mitochondria in vitro and in vivo, promoting normoxic hypoxia inducible factor-1α (HIF1α) activation and PHT. Methods and Results: Ucp2KO-PASMCs had lower Ca(2+)m than Ucp2WT-PASMCs at baseline and during histamine-stimulated ER-Ca(2+) release. Normoxic Ucp2KO-PASMCs had mitochondrial hyperpolarization, lower Ca(2+)-sensitive mitochondrial enzyme activity, reduced levels of mitochondrial reactive oxygen species and Krebs' cycle intermediates and increased resistance to apoptosis, mimicking the hypoxia-induced changes in Ucp2WT-PASMC. Ucp2KO mice spontaneously developed pulmonary vascular remodeling and PHT and exhibited a pseudo-hypoxic state with pulmonary vascular and systemic HIF1α activation (increased hematocrit), not exacerbated further by chronic hypoxia. Conclusions: This first description of the role of UCP2 in oxygen sensing and in PHT vascular remodeling may open a new window in biomarker and therapeutic strategies.
Circulation Research 05/2013; · 9.49 Impact Factor
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ABSTRACT: Current drug development in oncology is non-selective as it typically focuses on pathways essential for the survival of all dividing cells. The unique metabolic profile of cancer, which is characterized by increased glycolysis and suppressed mitochondrial glucose oxidation (GO) provides cancer cells with a proliferative advantage, conducive with apoptosis resistance and even increased angiogenesis. Recent evidence suggests that targeting the cancer-specific metabolic and mitochondrial remodeling may offer selectivity in cancer treatment. Pyruvate dehydrogenase kinase (PDK) is a mitochondrial enzyme that is activated in a variety of cancers and results in the selective inhibition of pyruvate dehydrogenase, a complex of enzymes that converts cytosolic pyruvate to mitochondrial acetyl-CoA, the substrate for the Krebs' cycle. Inhibition of PDK with either small interfering RNAs or the orphan drug dichloroacetate (DCA) shifts the metabolism of cancer cells from glycolysis to GO and reverses the suppression of mitochondria-dependent apoptosis. In addition, this therapeutic strategy increases the production of diffusible Krebs' cycle intermediates and mitochondria-derived reactive oxygen species, activating p53 or inhibiting pro-proliferative and pro-angiogenic transcription factors like nuclear factor of activated T cells and hypoxia-inducible factor 1α. These effects result in decreased tumor growth and angiogenesis in a variety of cancers with high selectivity. In a small but mechanistic clinical trial in patients with glioblastoma, a highly aggressive and vascular form of brain cancer, DCA decreased tumor angiogenesis and tumor growth, suggesting that metabolic-targeting therapies can be translated directly to patients. More recently, the M2 isoform of pyruvate kinase (PKM2), which is highly expressed in cancer, is associated with suppressed mitochondrial function. Similar to DCA, activation of PKM2 in many cancers results in increased mitochondrial function and decreased tumor growth. Therefore, reversing the mitochondrial suppression with metabolic-modulating drugs, like PDK inhibitors or PKM2 activators holds promise in the rapidly expanding field of metabolic oncology.
Frontiers in oncology. 01/2013; 3:38.
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ABSTRACT: Rationale: Right ventricular (RV) function is the most important determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Endothelin-1 (ET-1) receptor antagonists (ERAs) are approved therapies for PAH. It is unknown whether ERAs have effects on the RV, in addition to their vasodilating/anti-proliferative effects in pulmonary arteries. Objective: We hypothesized that the endothelin axis is upregulated in RV hypertrophy (RVH) and that ERAs have direct effects on the RV myocardium. Methods and Results: RV myocardial samples from 34 patients with RVH were compared to 16 non-hypertrophied RV samples; and from rats with normal RV versus RVH due to PAH. Confocal immunohistochemistry showed that RVH myocardial endothelin type A (but not type B) receptor and ET-1 protein levels were increased compared to the non-hypertrophied RVs and positively correlated with the degree of RVH (RV thickness/body surface area) (r(2)=0.838 and r(2)=0.818 respectively, p<0.01). These results were recapitulated in the rat model. In modified Langendorff perfusions, ERAs (BQ-123 and bosentan 10(-7,-6,-5M)) decreased contractility in the hypertrophied, but not normal RV, in a dose-dependent manner (p<0.01). Conclusions: Patients and rats with PAH have an up-regulation of the myocardial endothelin axis in RVH. This might be a compensatory mechanism to preserve RV contractility, as the afterload increases. ERAs use might potentially worsen RV function and this could explain some of the peripheral edema noted clinically with these agents. Further studies are required to evaluate the effects of ERA on the RV in patients with RVH and PAH.
Circulation Research 12/2012; · 9.49 Impact Factor
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ABSTRACT: The eukaryote's mitochondrial network is perhaps the cell's most sophisticated and dynamic responsive sensing system. Integrating metabolic, oxygen, or danger signals with inputs from other organelles, as well as local and systemic signals, mitochondria have a profound impact on vascular function in both health and disease. This review highlights recently discovered aspects of mitochondrial function (oxygen sensing, inflammation, autophagy, and apoptosis) and discusses their role in diseases of both systemic and pulmonary vessels. We also emphasize the role of mitochondria as therapeutic targets for vascular disease. We highlight the intriguing similarities of mitochondria-driven molecular mechanisms in terms of both pathogenesis and therapies in very diverse diseases, such as atherosclerosis, pulmonary hypertension, and cancer, to support the foundation of a new field in medicine: mitochondrial medicine. Expected final online publication date for the Annual Review of Physiology Volume 75 is February 10, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
Annual Review of Physiology 11/2012; · 20.83 Impact Factor
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ABSTRACT: BACKGROUND: Evidence suggestive of endoplasmic reticulum (ER) stress in the pulmonary arteries (PA) of patients with pulmonary arterial hypertension (PAH) has been described for decades but has never been therapeutically targeted. ER stress is a feature of many conditions associated with PAH like hypoxia, inflammation or loss-of-function mutations. ER stress signaling in the pulmonary circulation involves the activation of ATF-6, which via induction of the reticulin protein Nogo, can lead to the disruption of the functional ER-mitochondria unit and the increasingly recognized cancer-like metabolic shift in PAH that promotes proliferation and apoptosis resistance in the PA wall. We hypothesized that chemical chaperones known to suppress ER stress signaling, like 4-phenylbutyrate (PBA) or tauroursodeoxycholic acid (TUDCA), will inhibit the disruption of the ER-mitochondrial unit and prevent/reverse PAH. METHODS AND RESULTS: PBA in the drinking water both prevented and reversed chronic hypoxia induced pulmonary hypertension in mice, decreasing pulmonary vascular resistance, PA remodeling, right ventricular hypertrophy and improving functional capacity without affecting systemic hemodynamics. These results were replicated in the monocrotaline rat model. PBA and TUDCA improved ER stress indices in vivo and in vitro, decreased ATF6 activation (cleavage, nuclear localization, luciferase and downstream target expression) and inhibited the hypoxia-induced decrease in mitochondrial calcium and mitochondrial function. In addition these chemical chaperones suppressed proliferation and induced apoptosis in PA smooth muscle cells in vitro and in vivo. CONCLUSIONS: Attenuating ER stress with clinically used chemical chaperones may be a novel therapeutic strategy in pulmonary hypertension with high translational potential.
Circulation 11/2012; · 14.74 Impact Factor
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Chest 10/2012; 142(4):816-20. · 5.25 Impact Factor
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ABSTRACT: The biology of Pulmonary Arterial Hypertension (PAH) is full of mysteries and one of its longer standing ones has also intrigued and inspired both scientists and artists throughout history: the female sex. While affecting patients of all ages and both genders, PAH preferentially affects young women, suggesting that the female gender is a risk factor for PAH. Even in heritable PAH (HPAH) associated with autosomal dominant mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2), women after puberty are about 2.5 times more likely to develop PAH than males(1). In idiopathic PAH (IPAH) the female/male ratio ranges from 1.7:1 or 1.9:1 to 4.1:1 in three published PAH registries (the NIH registry in the 80s(2), the French registry(3) and the REVEAL registry(4) respectively). On the other hand, the disease can be more severe in men. Female animals with PAH tend to have lower pulmonary artery pressures and better outcomes compared to males(5) and similarly, male PAH patients have higher mortality than females(6). The basis for this apparent paradox remains unknown. (SELECT FULL TEXT TO CONTINUE).
Circulation 08/2012; 126(9):1016-9. · 14.74 Impact Factor
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ABSTRACT: The role of G protein-coupled receptors (GPCRs) in pulmonary arterial hypertension (PAH) is well recognized. GPCRs receptor agonists/antagonists aiming to offset the imbalance between vasoconstrictor/vasodilators seen in PAH constitute the basis of many currently used therapies. Implication of these receptors in PAH could be extended as our understanding of this vascular disease now goes beyond vascular tone, toward a proliferative vascular remodeling in which inflammation plays a prominent role. The breadth and depth of the GPCRs biology calls for a fresh look into their role in a complex disease like PAH that remains deadly and in urgent need for effective therapies.
Drug Discovery Today Disease Models 08/2012;
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ABSTRACT: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation and suppressed apoptosis of pulmonary artery smooth muscle cells (PASMC). This apoptosis resistance is characterized by PASMC mitochondrial hyperpolarization [in part, due to decreased pyruvate dehydrogenase (PDH) activity], decreased mitochondrial reactive oxygen species (mROS), downregulation of Kv1.5, increased [Ca(++)](i), and activation of the transcription factor nuclear factor of activated T cells (NFAT). Inflammatory cells are present within and around the remodeled arteries and patients with PAH have elevated levels of inflammatory cytokines, including tumor necrosis factor-α (TNFα). We hypothesized that the inflammatory cytokine TNFα inhibits PASMC PDH activity, inducing a PAH phenotype in normal PASMC. We exposed normal human PASMC to recombinant human TNFα and measured PDH activity. In TNFα-treated cells, PDH activity was significantly decreased. Similar to exogenous TNFα, endogenous TNFα secreted from activated human CD8(+) T cells, but not quiescent T cells, caused mitochondrial hyperpolarization, decreased mROS, decreased K(+) current, increased [Ca(++)](i), and activated NFAT in normal human PASMC. A TNFα antibody completely prevented, while recombinant TNFα mimicked the T cell-induced effects. In vivo, the TNFα antagonist etanercept prevented and reversed monocrotaline (MCT)-induced PAH. In a separate model, T cell deficient rats developed less severe MCT-induced PAH compared to their controls. We show that TNFα can inhibit PASMC PDH activity and induce a PAH phenotype. Our work supports the use of anti-inflammatory therapies for PAH.
Journal of Molecular Medicine 08/2011; 89(8):771-83. · 4.67 Impact Factor
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Gopinath Sutendra,
Peter Dromparis,
Paulette Wright,
Sébastien Bonnet,
Alois Haromy,
Zhengrong Hao,
M Sean McMurtry,
Marek Michalak,
Jean E Vance,
William C Sessa, Evangelos D Michelakis
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ABSTRACT: Pulmonary arterial hypertension (PAH) is caused by excessive proliferation of vascular cells, which occlude the lumen of pulmonary arteries (PAs) and lead to right ventricular failure. The cause of the vascular remodeling in PAH remains unknown, and the prognosis of PAH remains poor. Abnormal mitochondria in PAH PA smooth muscle cells (SMCs) suppress mitochondria-dependent apoptosis and contribute to the vascular remodeling. We hypothesized that early endoplasmic reticulum (ER) stress, which is associated with clinical triggers of PAH including hypoxia, bone morphogenetic protein receptor II mutations, and HIV/herpes simplex virus infections, explains the mitochondrial abnormalities and has a causal role in PAH. We showed in SMCs from mice that Nogo-B, a regulator of ER structure, was induced by hypoxia in SMCs of the PAs but not the systemic vasculature through activation of the ER stress-sensitive transcription factor ATF6. Nogo-B induction increased the distance between the ER and mitochondria and decreased ER-to-mitochondria phospholipid transfer and intramitochondrial calcium. In addition, we noted inhibition of calcium-sensitive mitochondrial enzymes, increased mitochondrial membrane potential, decreased mitochondrial reactive oxygen species, and decreased mitochondria-dependent apoptosis. Lack of Nogo-B in PASMCs from Nogo-A/B-/- mice prevented these hypoxia-induced changes in vitro and in vivo, resulting in complete resistance to PAH. Nogo-B in the serum and PAs of PAH patients was also increased. Therefore, triggers of PAH may induce Nogo-B, which disrupts the ER-mitochondria unit and suppresses apoptosis. This could rescue PASMCs from death during ER stress but enable the development of PAH through overproliferation. The disruption of the ER-mitochondria unit may be relevant to other diseases in which Nogo is implicated, such as cancer or neurodegeneration.
Science translational medicine 06/2011; 3(88):88ra55. · 7.80 Impact Factor
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ABSTRACT: Pulmonary arterial hypertension (PAH) is characterized by a hyperproliferative and anti-apoptotic diathesis within the vascular wall of the resistance pulmonary arteries, leading to vascular lumen occlusion, right ventricular failure, and death. Most current therapies show poor efficacy due to emphasis on vasodilation (rather than proliferation/apoptosis) and a lack of specificity to the pulmonary circulation. The multiple molecular abnormalities described in PAH are diverse and seemingly unrelated, calling for therapies that attack comprehensive, integrative mechanisms. Similar abnormalities also occur in cancer where a cancer-specific metabolic switch toward a non-hypoxic glycolytic phenotype is thought to be not only a result of several primary molecular or genetic abnormalities but also underlie many aspects of its resistance to apoptosis. In this paper, we review the evidence and propose that a metabolic, mitochondria-based theory can be applied in PAH. A pulmonary artery smooth muscle cell mitochondrial remodeling could integrate a number of diverse molecular abnormalities described in PAH and respond by orchestrating a switch toward a cancer-like glycolytic phenotype that drives resistance to apoptosis; via redox and calcium signals, this mitochondrial remodeling may also regulate critical transcription factors like HIF-1 and nuclear factor of activated T cells that have been described to play an important role in PAH. Because mitochondria in pulmonary arteries are quite different from mitochondria in systemic arteries, they could form the basis of relatively selective PAH therapies. This metabolic theory of PAH could facilitate the development of novel diagnostic and selective therapeutic approaches in this disease that remains deadly.
Journal of Molecular Medicine 10/2010; 88(10):1003-10. · 4.67 Impact Factor
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ABSTRACT: Pulmonary arterial hypertension is caused by excessive growth of vascular cells that eventually obliterate the pulmonary arterial lumen, causing right ventricular failure and premature death. Despite some available treatments, its prognosis remains poor, and the cause of the vascular remodeling remains unknown. The vascular smooth muscle cells that proliferate during pulmonary arterial hypertension are characterized by mitochondrial hyperpolarization, activation of the transcription factor NFAT (nuclear factor of activated T cells), and down-regulation of the voltage-gated potassium channel Kv1.5, all of which suppress apoptosis. We found that mice lacking the gene for the metabolic enzyme malonyl-coenzyme A (CoA) decarboxylase (MCD) do not show pulmonary vasoconstriction during exposure to acute hypoxia and do not develop pulmonary arterial hypertension during chronic hypoxia but have an otherwise normal phenotype. The lack of MCD results in an inhibition of fatty acid oxidation, which in turn promotes glucose oxidation and prevents the shift in metabolism toward glycolysis in the vascular media, which drives the development of pulmonary arterial hypertension in wild-type mice. Clinically used metabolic modulators that mimic the lack of MCD and its metabolic effects normalize the mitochondrial-NFAT-Kv1.5 defects and the resistance to apoptosis in the proliferated smooth muscle cells, reversing the pulmonary hypertension induced by hypoxia or monocrotaline in mice and rats, respectively. This study of fatty acid oxidation and MCD identifies a critical role for metabolism in both the normal pulmonary circulation (hypoxic pulmonary vasoconstriction) and pulmonary hypertension, pointing to several potential therapeutic targets for the treatment of this deadly disease.
Science translational medicine 08/2010; 2(44):44ra58. · 7.80 Impact Factor
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ABSTRACT: Pulmonary arterial hypertension (PAH) is a fatal orphan disease. The global epidemiology of PAH is not well known and encourages combined national and international efforts to enhance understanding of the disease. A global database will help unify investigators and patients to foster collaboration and knowledge.
Chest 06/2010; 137(6 Suppl):95S-101S. · 5.25 Impact Factor
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ABSTRACT: Despite the recognition of a critical role of the right ventricle (RV) in many aspects of cardiovascular medicine, there has been surprisingly little interest in right ventricular-targeted imaging and therapeutic approaches. Compared with the left ventricle, the RV has a different embryologic origin, undergoes a dramatic change during the transition from the fetal to the adult circulation and normally operates in a low resistance or impedance arterial system. Here, we review new insights on the pathophysiology, assessment and management of right ventricular failure.
Our understanding of the mechanisms underlying right ventricular failure has improved. As in the left ventricle, decrease in alpha-myosin heavy chain and a switch towards glycolysis from fatty acid oxidation is observed in the stressed RV, but the key question remains unanswered: why is the RV so much more vulnerable to failure upon afterload increase compared with the left ventricle? In assessing the RV, it is becoming increasingly important to consider the RV and pulmonary artery as a unit. New therapies that could specifically target the RV, such as metabolic modulators and phosphodiesterase type 5 inhibitors, are now being considered.
A better understanding of the molecular mechanisms of right ventricular failure will lead to the development of new strategies for the diagnosis and management of right ventricular failure. Right ventricular-targeted therapies are needed in a number of diseases in which only the RV fails.
Current opinion in cardiology 03/2010; 25(2):131-40. · 2.66 Impact Factor
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New England Journal of Medicine 11/2009; 361(19):1864-71. · 53.30 Impact Factor
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Circulation 09/2009; 120(11):992-1007. · 14.74 Impact Factor
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ABSTRACT: The remodeled vessel wall in many vascular diseases such as restenosis after injury is characterized by proliferative and apoptosis-resistant vascular smooth muscle cells. There is evidence that proproliferative and antiapoptotic states are characterized by a metabolic (glycolytic phenotype and hyperpolarized mitochondria) and electric (downregulation and inhibition of plasmalemmal K(+) channels) remodeling that involves activation of the Akt pathway. Dehydroepiandrosterone (DHEA) is a naturally occurring and clinically used steroid known to inhibit the Akt axis in cancer. We hypothesized that DHEA will prevent and reverse the remodeling that follows vascular injury.
We used cultured human carotid vascular smooth muscle cell and saphenous vein grafts in tissue culture, stimulated by platelet-derived growth factor to induce proliferation in vitro and the rat carotid injury model in vivo. DHEA decreased proliferation and increased vascular smooth muscle cell apoptosis in vitro and in vivo, reducing vascular remodeling while sparing healthy tissues after oral intake. Using pharmacological (agonists and antagonists of Akt and its downstream target glycogen-synthase-kinase-3beta [GSK-3beta]) and molecular (forced expression of constitutively active Akt1) approaches, we showed that the effects of DHEA were mediated by inhibition of Akt and subsequent activation of GSK-3beta, leading to mitochondrial depolarization, increased reactive oxygen species, activation of redox-sensitive plasmalemmal voltage-gated K(+) channels, and decreased [Ca(2+)](i). These functional changes were accompanied by sustained molecular effects toward the same direction; by decreasing [Ca(2+)](i) and inhibiting GSK-3beta, DHEA inhibited the nuclear factor of activated T cells transcription factor, thus increasing expression of Kv channels (Kv1.5) and contributing to sustained mitochondrial depolarization. These results were independent of any steroid-related effects because they were not altered by androgen and estrogen inhibitors but involved a membrane G protein-coupled receptor.
We suggest that the orally available DHEA might be an attractive candidate for the treatment of systemic vascular remodeling, including restenosis, and we propose a novel mechanism of action for this important hormone and drug.
Circulation 09/2009; 120(13):1231-40. · 14.74 Impact Factor
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ABSTRACT: Both our first and our last breath are associated with inhibition of voltage-gated K+ channels (Kv). Upon our first breath, the transition from the fetal to the adult circulation is driven by the contraction of the ductus arteriosus (DA); which is mediated by the closure of redox-sensitive DA smooth muscle cell Kv channels, causing membrane depolarization, influx of Ca(++) and DA contraction (18). For most of us, our last breath will take place during a cardiac arrest, a condition precipitated or initiated, at least in part, by inhibition or deficiency of myocardial Kv channels (6, 24). Key words: Electrical remodeling, Redox, Metabolic remodeling, Hypertrophy.
AJP Cell Physiology 07/2009; 297(2):C231-4. · 3.54 Impact Factor
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Paul M Hassoun,
Luc Mouthon,
Joan A Barberà,
Saadia Eddahibi,
Sonia C Flores,
Friedrich Grimminger,
Peter Lloyd Jones,
Michael L Maitland, Evangelos D Michelakis,
Nicholas W Morrell,
John H Newman,
Marlene Rabinovitch,
Ralph Schermuly,
Kurt R Stenmark,
Norbert F Voelkel,
Jason X-J Yuan,
Marc Humbert
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ABSTRACT: Inflammatory processes are prominent in various types of human and experimental pulmonary hypertension (PH) and are increasingly recognized as major pathogenic components of pulmonary vascular remodeling. Macrophages, T and B lymphocytes, and dendritic cells are present in the vascular lesions of PH, whether in idiopathic pulmonary arterial hypertension (PAH) or PAH related to more classical forms of inflammatory syndromes such as connective tissue diseases, human immunodeficiency virus (HIV), or other viral etiologies. Similarly, the presence of circulating chemokines and cytokines, viral protein components (e.g., HIV-1 Nef), and increased expression of growth (such as vascular endothelial growth factor and platelet-derived growth factor) and transcriptional (e.g., nuclear factor of activated T cells or NFAT) factors in these patients are thought to contribute directly to further recruitment of inflammatory cells and proliferation of smooth muscle and endothelial cells. Other processes, such as mitochondrial and ion channel dysregulation, seem to convey a state of cellular resistance to apoptosis; this has recently emerged as a necessary event in the pathogenesis of pulmonary vascular remodeling. Thus, the recognition of complex inflammatory disturbances in the vascular remodeling process offers potential specific targets for therapy and has recently led to clinical trials investigating, for example, the use of tyrosine kinase inhibitors. This paper provides an overview of specific inflammatory pathways involving cells, chemokines and cytokines, cellular dysfunctions, growth factors, and viral proteins, highlighting their potential role in pulmonary vascular remodeling and the possibility of future targeted therapy.
Journal of the American College of Cardiology 06/2009; 54(1 Suppl):S10-9. · 14.16 Impact Factor
