Coronary artery dysfunction in OSA: Role of mineralocorticoid receptors

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Abstract Obstructive sleep apnea (OSA) is a prevalent condition worldwide, especially in people with obesity, and is an independent risk factor for cardiovascular disease (CVD), including coronary microvascular dysfunction (CMD). Current available OSA treatments have not consistently detected the anticipated improvements in CVD and CMD, suggesting the need for adjuvant therapies aimed at the mechanisms underlying the core disturbances induced by OSA. As such, OSA-induced renin-angiotensin-aldosterone system (RAAS) activation may trigger excessive mineralocorticoid receptor (MR) signaling, which play a major role in endothelial dysfunction and atherosclerosis. Thus, the hypothesis is that OSA-induced CMD is mediated, at least in part, by MR dependent mechanisms. To examine the role of MR in OSA-induced CMD, obese C57Bl/6 male and female mice will be exposed to intermittent hypoxia (IH) during the rest period, a mouse model of OSA, for 6 weeks (short-term) and 16 weeks (long-term) and treated with the conventional steroidal MR antagonist (spironolactone) or the novel non-steroidal MR antagonist (finerenone) to evaluate the MR-dependent reversibility of IH-induced CMD (SA1). To investigate whether MR inhibition can accelerate CMD recovery, mice will be exposed to short-and long-term IH followed by 12 weeks of normoxia (IH cessation – simulating ideal OSA treatment) with or without concurrent treatment with MR antagonists (SA2). To examine the role of vascular cell-specific MR, transgenic mice with endothelial cell (EC)-specific and smooth muscle cell (SMC)-specific deletions of MR will be exposed to long- term IH (SA3). Coronary artery function will be evaluated in vivo and ex vivo in addition to heart function, blood pressure and metabolic assessments. Moreover, immunohistological analysis of the coronary vessels, along with gene networks expression dynamics among different coronary artery cell populations will be evaluated using single-nucleus RNA sequencing (snRNA-seq). Male and female mice will be fed a high-fat or control diet for 8 weeks then housed in environmental chambers for IH exposures (alternating 6.1% FIO2/21.0%FIO2 90 sec:90 sec, for 6 or 16 weeks during 12 daylight hours, and treated with spironolactone (20mg/kg), finerenone (1mg/kg), or placebo. IH cessation protocol consists of removing the exposed animals for the IH chambers and left under normoxic conditions for 12 weeks. Heart function will be examined via echocardiography, while blood pressure and coronary flow reserve velocity (CFVR) will be assessed using tail cuff method/telemetry and doppler flow velocity system, respectively. Additionally, Insulin tolerance test and fasting blood and lipid profiles will be evaluated. After euthanasia, coronary arteries will be excised and mounted on a wire myograph for functional studies or processed for immunohistological analyses (including intima-media thickness, collagen fiber distribution, and indices of oxidative stress and inflammation) or snRNA-seq. The proposed studies will elucidate the role of MR signaling in OSA-mediated coronary artery dysfunction and potential approaches to enhance CMD reversibility, thereby enabling MR antagonists as biologically plausible therapeutic targets in OSA patients.