Unlooked-for significance of cardiac versus vascular effects of endothelin-1 in the pathophysiology of pulmonary arterial hypertension.

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. The 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. 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 mito-gen 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 …