Endothelin Axis Is Upregulated in Human and Rat Right Ventricular Hypertrophy

Nagendran, Jayan; Sutendra, Gopinath; Paterson, Ian; Champion, Hunter C.; Webster, Linda; Chiu, Brian; Haromy, Alois; Rebeyka, Ivan M.; Ross, David B.; Michelakis, Evangelos D.

doi:10.1161/circresaha.111.300448

Cited by 71 publications

(61 citation statements)

References 51 publications

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“…28 Recent work using rats with secondary PAH induced by ischemic heart failure has also shown that RV dysfunction is not improved by bosentan treatment. 29 The study by Nagendran et al 26 may partly explain why treatment with bosentan provides no significant improvement of RV dysfunction in PAH observed in those studies.…”

Section: Circulation Researchmentioning

confidence: 94%

“…25 Current treatment guidelines recommend these ERAs, especially for PAH patients in the World Health Organization (WHO) functional class III. 19 In the current issue of Circulation Research, Nagendran et al 26 demonstrate a compensatory role for the upregulated ET-1 axis to preserve RV contractility in RV hypertrophy. The authors found that bosentan and cyclo(Trp-Asp-Pro-ValLeu) (ET A receptor antagonist) decreased cardiac contractility in hypertrophied, but not normal rat RVs in a concentrationdependent manner.…”

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confidence: 95%

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Unlooked-for Significance of Cardiac Versus Vascular Effects of Endothelin-1 in the Pathophysiology of Pulmonary Arterial Hypertension

Taguchi

Hattori

2013

Circulation Research

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P ulmonary arterial hypertension (PAH) is a progressive and devastating condition that is characterized by pulmonary vascular remodeling resulting in increased pulmonary vascular resistance and raised pulmonary arterial pressure, eventually leading to right ventricular (RV) failure and premature death. 1,2 PAH carries a poor prognosis. Even in the current treatment era, the average life expectancy of PAH patients after diagnosis is estimated at 5 to 7 years, with significant morbidity. 3-5Article, see p 347The pathobiology of PAH remains incompletely understood. The process of pulmonary vascular remodeling involves pathological changes in the intima, media, and adventitial layers of the vessel wall, and each cell type, including endothelial, smooth muscle, and fibroblast, in the pulmonary vascular wall plays a specific role in the pathogenesis. 6 Both vascular endothelial and smooth muscle cells exhibit an abnormal growth phenotype, which is characterized by excess cellular proliferation and apoptosis resistance.7 Disorganized endothelial cell proliferation leads to the formation of glomeruloid structure known as the plexiform lesions, which are common pathological features of the pulmonary vessels of PAH patients and are not found in the diseases of the systemic circulation. 8,9 In addition, a characteristic feature of severe pulmonary hypertension is the formation of a layer of myofibroblasts and extracellular matrix between the endothelium and the internal elastic lamina, termed neointima. 6 These abnormalities in resident vascular cells, in concert with vasoconstriction, thrombosis, and inflammation, contribute to physical narrowing of the distal part of the pulmonary arterial tree. Such narrowing results in a remarkable increase in pulmonary vascular resistance, leading ultimately to the chronic and progressive elevation of pulmonary arterial pressure.Endothelin-1 (ET-1) is a potent vasoconstrictor and mitogen 10 that has been implicated in the pathogenesis and progression of PAH. Patients with idiopathic PAH show higher circulating levels of ET-1 and higher arterial-to-venous ratios of ET-1 than healthy control.11 This may represent increased production of ET-1 by the lung or reduced clearance of ET-1 by the lung. The lung is an important site of ET-1 production with an mRNA level of ET-1 5 times more abundant than those seen in other organs.12 Increased lung ET-1 levels have demonstrated in PAH patients and in animal models of PAH.13-15 Consistent with these findings is the observation that immunoreactivity for ET-converting enzyme-1 is augmented in the endothelium of pulmonary arteries from PAH patients. 16 Furthermore, a rise in mRNA levels of 2 ET receptors, ET A and ET B , has been shown in lungs of rats with hypoxia-induced PAH.17 Therefore, nearly every component of the ET system in lungs seems to be upregulated in PAH.ET-1 can be involved in the development of lung vascular and interstitial remodeling (Figure). Thus, ET-1 promotes vascular smooth muscle cell proliferation through both ET A and ET B...

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Section: Circulation Researchmentioning

confidence: 94%

mentioning

confidence: 95%

Unlooked-for Significance of Cardiac Versus Vascular Effects of Endothelin-1 in the Pathophysiology of Pulmonary Arterial Hypertension

Taguchi

Hattori

2013

Circulation Research

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“…For example, sildenafil has been shown to increase RV inotropy, 37 and conversely agents like bosentan exert a negative effect on RV function. 38 We propose that when evaluating the effects of a pulmonary hypertension drug, researchers should look for a concomitant improvement in RV function. Alzoubi et al 39 reported that dehydroepiandrosterone (DHEA) reduced the severity and frequency of lung vascular occlusive lesions in the SuHx rat model of severe PAH, but, most importantly, treatment with DHEA also restored RV function, and this improvement was associated with recovery of the RV capillary density and reduced expression of apoptosis markers.…”

Section: The Lung Circulation-rv Axis: Implications For Future Therapiesmentioning

confidence: 99%

The Need to Recognize the Pulmonary Circulation and the Right Ventricle as an Integrated Functional Unit: Facts and Hypotheses (2013 Grover Conference series)

2015

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For many patients with severe pulmonary arterial hypertension, heart failure-and, in particular, right heart failure-is the final chapter of their chronic illness. Targeted therapy for pulmonary hypertension is effective only if the right ventricular ejection fraction is maintained or improved. Because improvement of right heart function and reversal of right heart failure are treatment goals, it is important to investigate the cellular and molecular mechanisms that cause right heart failure. Here, we propose that right ventricular capillary rarefaction is an important hallmark of right heart failure and consider that the "sick lung circulation" and the pressure-overloaded right ventricle constitute a functional unit.

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“…Endothelin Axis in RVH (p 347) 6 Drugs for lowering pulmonary artery blood pressure could have detrimental effects on the heart, say Nagendran et al…”

Section: Sarcolemmal Invaginations and Nuclear Camentioning

confidence: 99%

Circulation Research “In This Issue” Anthology

Williams¹

2014

Circulation Research

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Endothelin Axis Is Upregulated in Human and Rat Right Ventricular Hypertrophy

Abstract: −7,−6,−5 mol/L) decreased contractility in the hypertrophied, but not normal RV, in a dose-dependent manner (P<0.01). Conclusions:

Cited by 71 publications

References 51 publications

Unlooked-for Significance of Cardiac Versus Vascular Effects of Endothelin-1 in the Pathophysiology of Pulmonary Arterial Hypertension

Unlooked-for Significance of Cardiac Versus Vascular Effects of Endothelin-1 in the Pathophysiology of Pulmonary Arterial Hypertension

The Need to Recognize the Pulmonary Circulation and the Right Ventricle as an Integrated Functional Unit: Facts and Hypotheses (2013 Grover Conference series)

Circulation Research “In This Issue” Anthology

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