Bosentan attenuates right ventricular hypertrophy and fibrosis in normobaric hypoxia model of pulmonary hypertension

Choudhary, Gaurav; Troncales, Frederick; Martin, Douglas W.; Harrington, Elizabeth O.; Klinger, James R.

doi:10.1016/j.healun.2011.03.010

Cited by 38 publications

(33 citation statements)

References 32 publications

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“…Thus, just like the complex or even conflicting reports on the role of PKC in mediating myocardial protection from ischemia (40), ET-1-PKC interactions are complex. However, recent and growing evidence suggests that PKCd may play the predominant role in ET-1-mediated constriction and blood pressure elevation (41,42). Consistent with these studies, we found that a PKCd-inhibitory peptide significantly attenuated ET-1-induced eNOS mitochondrial redistribution and preserved mitochondrial bioenergetics.…”

Section: Discussionsupporting

confidence: 90%

Endothelin-1 Induces a Glycolytic Switch in Pulmonary Arterial Endothelial Cells via the Mitochondrial Translocation of Endothelial Nitric Oxide Synthase

Sun

Kumar

Sharma

et al. 2014

Am J Respir Cell Mol Biol

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Recent studies have indicated that, during the development of pulmonary hypertension (PH), there is a switch from oxidative phosphorylation to glycolysis in the pulmonary endothelium. However, the mechanisms underlying this phenomenon have not been elucidated. Endothelin (ET)-1, an endothelial-derived vasoconstrictor peptide, is increased in PH, and has been shown to play an important role in the oxidative stress associated with PH. Thus, in this study, we investigated whether there was a potential link between increases in ET-1 and mitochondrial remodeling. Our data indicate that ET-1 induces the redistribution of endothelial nitric oxide synthase (eNOS) from the plasma membrane to the mitochondria in pulmonary arterial endothelial cells, and that this was dependent on eNOS uncoupling. We also found that ET-1 disturbed carnitine metabolism, resulting in the attenuation of mitochondrial bioenergetics. However, ATP levels were unchanged due to a compensatory increase in glycolysis. Further mechanistic investigations demonstrated that ET-1 mediated the redistribution of eNOS via the phosphorylation of eNOS at Thr495 by protein kinase C d. In addition, the glycolytic switch appeared to be dependent on mitochondrial-derived reactive oxygen species that led to the activation of hypoxia-inducible factor signaling. Finally, the cell culture data were confirmed in vivo using the monocrotaline rat model of PH. Thus, we conclude that ET-1 induces a glycolytic switch in pulmonary arterial endothelial cells via the redistribution of uncoupled eNOS to the mitochondria, and that preventing this event may be an approach for the treatment of PH.Keywords: mitochondrial bioenergetics; endothelial nitric oxide synthase uncoupling; protein kinase C d; peroxynitrite; superoxide Clinical RelevanceIt is becoming increasingly clear that the Warburg effect plays an important role in the development of pulmonary hypertension (PH). However, mechanisms underlying the glycolytic switch are unresolved. Our data demonstrate that endothelin-1, which is increased in PH, is capable of inducing aerobic glycolysis in pulmonary endothelial cells.Mitochondria are essential for energy metabolism through their ability to generate cellular ATP through oxidative phosphorylation. Increasing evidence suggests that mitochondrial remodeling is a critical event in a number of cardiovascular diseases, including pulmonary hypertension (PH) (1, 2). PH is a fatal disease characterized by pathologic vascular remodeling, which eventually leads to right ventricular failure and death. Several decades ago, Warburg (3) identified

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Section: Discussionsupporting

confidence: 90%

Endothelin-1 Induces a Glycolytic Switch in Pulmonary Arterial Endothelial Cells via the Mitochondrial Translocation of Endothelial Nitric Oxide Synthase

Sun

Kumar

Sharma

et al. 2014

Am J Respir Cell Mol Biol

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“…54 Finally, bosentan reduced hypertrophy and fibrosis, including collagen deposition in animal models of heart disease. 55 The development of cardiac fibrosis and hypertrophy in response to Ang II is impaired in mice with vascular endothelial cell-specific ET-1 deficiency. 56 These results are consistent with observations that Ang-II induces ET-1 via extracellular signal-regulated kinase and reactive oxygen species and the serum-responsive transcription factor myocardin-related transcription factor (MRTF) A.…”

Section: Endothelin-1mentioning

confidence: 99%

Getting to the Heart of the Matter

Leask

2015

Circulation Research

296

147

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Fibrotic diseases are a significant global burden for which there are limited treatment options. The effector cells of fibrosis are activated fibroblasts called myofibroblasts, a highly contractile cell type characterized by the appearance of α-smooth muscle actin stress fibers. The underlying mechanism behind myofibroblast differentiation and persistence has been under much investigation and is known to involve a complex signaling network involving transforming growth factor-β, endothelin-1, angiotensin II, CCN2 (connective tissue growth factor), and platelet-derived growth factor. This review addresses the contribution of these signaling molecules to cardiac fibrosis.

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“…In pulmonary hypertension models induced by chronic hypoxia or monocrotaline, bosentan attenuated the increase in pulmonary artery pressures, prevented pulmonary vascular remodeling, and decreased RVH [66][67][68][69]. In terms of cardiac tissue, bosentan inhibits RV collagen expression in rats exposed to chronic hypoxia [68].…”

Section: Bosentanmentioning

confidence: 99%

Clinical Pharmacology of Endothelin Receptor Antagonists Used in the Treatment of Pulmonary Arterial Hypertension

Chaumais

Guignabert

Savale

et al. 2014

Am J Cardiovasc Drugs

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Pulmonary arterial hypertension (PAH) is a devastating life-threatening disorder characterized by elevated pulmonary vascular resistance leading to elevated pulmonary arterial pressures, right ventricular failure, and ultimately death. Vascular endothelial cells mainly produce and secrete endothelin (ET-1) in vessels that lead to a potent and long-lasting vasoconstrictive effect in pulmonary arterial smooth muscle cells. Along with its strong vasoconstrictive action, ET-1 can promote smooth muscle cell proliferation. Thus, ET-1 blockers have attracted attention as an antihypertensive drug, and the ET-1 signaling system has paved a new therapeutic avenue for the treatment of PAH. We outline the current understanding of not only the pathogenic role played by ET-1 signaling systems in the pathogenesis of PH but also the clinical pharmacology of endothelin receptor antagonists (ERA) used in the treatment of PAH.

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Bosentan attenuates right ventricular hypertrophy and fibrosis in normobaric hypoxia model of pulmonary hypertension

Cited by 38 publications

References 32 publications

Endothelin-1 Induces a Glycolytic Switch in Pulmonary Arterial Endothelial Cells via the Mitochondrial Translocation of Endothelial Nitric Oxide Synthase

Endothelin-1 Induces a Glycolytic Switch in Pulmonary Arterial Endothelial Cells via the Mitochondrial Translocation of Endothelial Nitric Oxide Synthase

Getting to the Heart of the Matter

Clinical Pharmacology of Endothelin Receptor Antagonists Used in the Treatment of Pulmonary Arterial Hypertension

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