Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial Cells

Abstract

Hypoxia-induced pulmonary vascular constriction and structure remodeling are the main causes of hypoxic pulmonary hypertension. In the present study, an adeno-associated virus vector, containing Tie2 promoter and hypoxia response elements, was designed and named HTSFcAng(1-7). Its targeting, hypoxic inducibility, and vascular relaxation were examined in vitro, and its therapeutic effects on hypobaric hypoxia-induced pulmonary hypertension were examined in rats. Transfection of HTSFcAng(1-7) specifically increased the expression of angiotensin-(1-7) in endothelial cells in normoxia. Hypoxia increased the expression of angiotensin-(1-7) in HTSFcAng(1-7)-transfected endothelial cells. The condition medium from HTSFcAng(1-7)-transfected endothelial cells inhibited the hypoxia-induced proliferation of pulmonary artery smooth muscle cells, relaxed the pulmonary artery rings, totally inhibited hypoxia-induced early contraction, enhanced maximum relaxation, and reversed phase II constriction to sustained relaxation. In hypoxic pulmonary hypertension rats, treatment with HTSFcAng(1-7) by nasal drip adeno-associated virus significantly reversed hypoxia-induced hemodynamic changes and pulmonary artery-wall remodeling, accompanied by the concomitant overexpression of angiotensin-(1-7), mainly in the endothelial cells in the lung. Therefore, hypoxia-inducible overexpression of angiotensin-(1-7) in pulmonary endothelial cells may be a potential strategy for the gene therapy of hypoxic pulmonary hypertension.

ACE2, angiotensin 1-7 and skeletal muscle: review in the era of COVID-19

“…Previous studies have indicated that Ang 1-7 antagonises these cellular mechanisms of Ang II in mediating insulin resistance primarily through a receptor, Mas. First, multiple lines of evidence have confirmed that Ang 1-7 could restore endothelial dysfunction in various organs by counteracting Ang II-induced impairment of NO production [84][85][86][87][88][89][90][91]. The involvement of Mas in Ang 1-7-induced endothelial protection has been shown by endothelial dysfunction in rodents with genetic [92][93][94] or pharmacological blockade of Mas [95].…”

Construction and analysis of the abnormal lncRNA–miRNA–mRNA network in hypoxic pulmonary hypertension

“…Hypoxic pulmonary hypertension (HPH) is generally characterized as atypical contraction and remodelling of the small pulmonary vessels caused by abnormal activation of the local pulmonary vasoconstriction system and proliferation of pulmonary smooth muscle cells [ 1 ]. HPH is common in almost all advanced stages of chronic lung disease, and the prevalence of HPH has increased in both adults and children in recent years [ 2 ].…”

Alternative RAS in Various Hypoxic Conditions: From Myocardial Infarction to COVID-19

“…The situation regarding hypoxia is similar, without any human trials. In the animal models of hypoxia-induced pulmonary arterial hypertension [ 229 , 230 , 231 , 232 ], treatment with recombinant ACE2 or Ang(1-7) improved symptoms of pulmonary arterial hypertension (PAH) (lowered pulmonary arterial pressure, lung fibrosis, inflammation), however, there is a lack of evidence about the involvement of ACE2 in the models including both hypoxia and COPD. It is also hard to evaluate how hypoxia alone regulates ACE2/Ang(1-7) expression.…”

“…Several rat and murine models suggest its beneficial effects in amelioration of monocrotaline-induced PAH symptoms. Animals overexpressing ACE2 [ 230 , 251 , 258 , 259 ] and Ang(1-7) [ 229 ] had lower right ventricular systolic pressure and pulmonary arterial pressure, less pronounced right ventricular hypertrophy and pulmonary artery remodeling and better hemodynamics in PAH. In a swine model of HPH, similar effects were observed after treatment with recombinant ACE2 [ 231 ].…”