ACE2 overexpression in corticotropin-releasing-hormone cells offers protection against pulmonary hypertension

Abstract

BackgroundPulmonary hypertension (PH), characterized by elevated pulmonary pressure and right heart failure, is a systemic disease involving inappropriate sympathetic activation and an impaired gut-brain-lung axis. Global overexpression of angiotensin converting enzyme 2 (ACE2), a cardiopulmonary protective enzyme of the renin-angiotensin system, attenuates PH induced by chronic hypoxia. Neurons within the paraventricular nucleus of the hypothalamus (PVN) that synthesize corticotropin-releasing hormone (CRH) are activated by stressors, like hypoxia, and this activation augments sympathetic outflow to cardiovascular tissues. These data coupled with our observations that ACE2 overexpression in CRH cells (CRH-ACE2KI mice) decreases anxiety-like behavior via suppression of hypothalamic–pituitary–adrenal (HPA) axis activity by decreasing CRH synthesis, led us to hypothesize that selective ACE2 overexpression in CRH neurons would protect against hypoxia-induced PH.MethodsCRH-ACE2KI and WT male and female mice were exposed to chronic hypoxia (10%O2) or normoxia (21%O2) for 4 weeks in a ventilated chamber with continuous monitoring of oxygen and carbon dioxide concentrations (n = 7–10/group). Pulmonary hemodynamics were measured with Millar pressure catheters then tissues were collected for histological analyses.ResultsChronic hypoxia induced a significant increase (36.4%) in right ventricular (RV) systolic pressure (RVSP) in WT mice, which was not observed in CRH-ACE2KI mice. No significant differences in RVSP were observed between male and female mice in any of the groups.ConclusionOverexpression of ACE2 in CRH cells was protective against hypoxia-induced PH. Since the majority of expression of CRH is in brain nuclei such as paraventricular nucleus of the hypothalamus (PVN) and/or central nucleus of the amygdala (CeA) these data indicate that the protective effects of ACE2 are, at least in part, centrally mediated. This contributes to the systemic nature of PH disease and that CRH neurons may play an important role in PH.

Pulmonary Hypertension: Pharmacological and Non-Pharmacological Therapies

“…Electroacupuncture also reduces sympathetic activity through other central pathways. For instance, hyperactivity of sympathetic neurons within the hypothalamic PVN and their ensuing connections with the rVLM is implicated in multiple diseases, including in models of hypoxiainduced PH [231][232][233][234]. Elevated levels of corticotropin-releasing hormone (CRH) synthesis and neuronal activity contribute to this sympathetic overactivity, including in disease models of PH [231,232].…”

“…For instance, hyperactivity of sympathetic neurons within the hypothalamic PVN and their ensuing connections with the rVLM is implicated in multiple diseases, including in models of hypoxiainduced PH [231][232][233][234]. Elevated levels of corticotropin-releasing hormone (CRH) synthesis and neuronal activity contribute to this sympathetic overactivity, including in disease models of PH [231,232]. Moreover, CRH neurons observed in the PVN and NTS are activated during acute hypoxic conditions leading to increased sympathetic outflow [235][236][237][238][239].…”

Angiotensin-Converting Enzyme 2 (ACE2) Signaling in Pulmonary Arterial Hypertension: Underpinning Mechanisms and Potential Targeting Strategies

“…Future studies need to probe the role of soluble ACE2 and its regulation via post-translational modifications in the pathophysiology of PAH. Thirdly, the expression and function of ACE2 besides the pulmonary system, including the central nervous system and the gastrointestinal system, and its potentially protective effects against PAH should be investigated [52][53][54]. Furthermore, the interaction of ACE2 with other signaling pathways, such as the apelinergic system, need to be explored and therapeutically exploited [55].…”