R-propranolol  Promotes lipid synthesis via a novel, non-adrenergic pathway to treat sickle cell cardiomyopathy Free

Background/Hypothesis: Sickle cell cardiomyopathy (SCC) is characterized by diastolic dysfunction, heart failure, and ventricular arrhythmias (VT). β-blockers such as propranolol are cardioprotective and reduce inflammation, but whether this benefit is derived from adrenergic signaling is unclear. Based on our prior work on the role of IL-18 and inflammation in SCC, we hypothesized that r-propranolol (enantiomer with 100-fold less adrenergic activity) attenuates SCC via an adrenergic-independent pathway. Given propranolol's established role in lipid membrane remodeling, we further evaluated whether r-propranolol induces lipid synthesis and reduces membrane permeability resulting in reduced cardiac inflammation.

Methods: We used human coronary artery endothelial cells (HCAEC) and Townes sickle (SCD) mice (and controls) for all experiments and treated with vehicle, r-propranolol (10uM for cells and 10mg/ml for mice, IP), a known SREBP1 agonist (T0901317, 10uM for cells and 10mg/ml for mice, IP), and a known SREBP1 inhibitor (fatostatin, 1uM for cells and 10mg/ml for mice, IP) for 24 hours for cells and daily (7dd total) for mice. SREBP1 and IL-18 activation were assessed via immunofluorescence, western blotting, and RT-qPCR. To assess the therapeutic impact of r-propranolol (10mg/ml, 7dd, IP), we also performed echocardiography, cardiac electrophysiology, and histopathology.

Results: Exposure to r-propanolol significantly reversed hemin-induced reductions in normalized resistance, suggesting reduced membrane permeability. As expected T0901317 activated SREBP1 in HCAEC unlike fatostatin. R-propranolol also activated SREBP1 in cells as measured by western blots and immunofluorescence. In comparison to controls, sickle mice showed higher IL-18 expression levels and reduced SREBP1 activity (reduced cleaved SREBP1 levels, increased stearoyl-CoA desaturase 1 or SCD1 levels- a known target for SREBP1) which was reversed by R-propranolol and fatostatin. Sickle mice that received r-propranolol also displayed reduced diastolic dysfunction and attenuated IL–18–induced action potential duration (APD) prolongation and VT.

Conclusion: R-propranolol is a novel therapeutic for sickle cardiomyopathy in mice. Mechanistically, r-propranolol induces SREBP1 activation, resulting in reduced IL-18 activation and cardiac inflammation.