Patients with obstructive sleep apnea (OSA) exhibit poor prognosis after myocardial infarction (MI). Intermittent hypoxia (IH), the hallmark feature of OSA, promotes sympathetic hyperactivity and systemic insulin resistance, and has been identified as a major contributor to post-MI cardiac remodeling and contractile dysfunction.

We hypothesize that sympathetic hyperactivity and metabolic alterations induced by IH participate in the aggravation of ischemic cardiomyopathy via activation of G protein-coupled receptors kinase (GRK2), known to be involved in adrenergic desensitization. To investigate the detrimental role of GRK2, we used paroxetine, described as a specific GRK2 inhibitor.

MI is induced in C57bl6 mice by permanent ligation of the left coronary artery. Mice are then randomized to IH (21–5% FiO₂, 60 s cycle, 8h/day) or normoxia (N) for up to 6 weeks. After two weeks exposure, mice are treated with a GRK2 inhibitor, paroxetine (5mg/kg/d), or 25% DMSO (Alzet® pumps). Longitudinal follow-up of mice includes evaluation of sympathetic activity (spectral analysis of heart rate variability (HRV), systemic insulin sensitivity (dynamic insulin tolerance test) and determination of cardiac function/remodeling (echocardiography). At the end of the protocol, cardiac interstitial fibrosis and hypertrophy are evaluated by RT-qPCR and histology (Sirius Red and WGA staining). Assessment of insulin signaling pathway is performed by Western blot 15min after injection of NaCl or insulin (0,5UI/kg).

Compared to N condition, IH worsens post-MI contractile dysfunction (i.e. ejection fraction), which is prevented by paroxetine treatment. Whereas IH does not induce cardiomyocyte hypertrophy, it results in increased cardiac interstitial fibrosis and apoptosis, which are limited by paroxetine. Our results evidence an IH-induced sympathetic overactivity in MI mice [i.e. increase in LF (Low Frequencies), derived from HRV analysis]. Paroxetine abolishes the increase in LF in MI-IH condition and restores mRNA expression of β1 and β2 adrenergic receptors. Finally, IH induces post-MI systemic insulin resistance compared to MI-N condition, which is prevented by paroxetine. This beneficial effect of paroxetine could result from improvement of insulin signaling in liver and muscle of MI-IH mice (pIRβ & pAKT).

Inhibition of GRK2 by paroxetine limits IH-induced worsening of ischemic cardiomyopathy, by limiting both cardiac sympathetic hyperactivity and systemic insulin resistance.