A G-protein-biased S1P1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome

Abstract

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSAimC_ST_ABSHeart failure with preserved ejection fraction (HFpEF) is a major cause of death worldwide with no approved treatment. Left ventricular hypertrophy (LVH) and diastolic dysfunction represent the structural and functional components of HFpEF, respectively. Endothelial dysfunction is prevalent in HFpEF and predicts cardiovascular events. We investigated if SAR247799, a G-protein-biased sphingosine-1-phosphate receptor 1 (S1P1) agonist with endothelial-protective properties, could improve cardiac and renal functions in a rat model of metabolic syndrome LVH and diastolic function. Methods31- and 65-week-old obese ZSF1 (Ob-ZSF1) rats, representing young and old animals with LVH and diastolic dysfunction, were randomized to a chow diet containing 0.025% (w/w) of SAR247799, or control (CTRL) chow for 4 weeks. Age-matched lean ZSF1 (Le-ZSF1) rats were fed control chow. Echocardiography, telemetry, biochemical and histological analysis were performed to evaluate the effect of SAR247799. ResultsEchocardiography revealed that Ob-ZSF1 rats, in contrast to Le-ZSF1 rats, developed progressive diastolic dysfunction and cardiac hypertrophy with age. SAR247799 blunted the progression of diastolic dysfunction in young and old animals: in young animals E/e was evaluated at 21.8 {+/-} 1.4 for Ob-ZSF1-CTRL, 19.5 {+/-} 1.2 for Ob-ZSF1-SAR247799 p<0.01, and 19.5 {+/-} 2.3 for Le-ZSF1-CTRL (median {+/-} IQR). In old animals E/e was evaluated at 23.15 {+/-} 4.45 for Ob-ZSF1-CTRL, 19.5 {+/-} 5 for Ob-ZSF1-SAR247799 p<0.01, and 16.69 {+/-} 1.7 for Le-ZSF1-CTRL, p<0.01 (median {+/-} IQR). In old animals, SAR247799 reduced cardiac hypertrophy (mean {+/-} SEM of heart weight/tibia length 0.053 {+/-} 0.001 for Ob-ZSF1-CTRL vs 0.046 {+/-} 0.002 for Ob-ZSF1-SAR247799 p<0.01, Le-ZSF1-CTRL 0.035 {+/-} 0.001) and myocardial perivascular collagen content (p<0.001), independently of any changes in microvascular density. In young animals, SAR247799 improved endothelial function as assessed by the very low frequency bands of systolic blood pressure variability (mean {+/-} SEM 67.8 {+/-} 3.41 for Ob-ZSF1-CTRL 55.8 {+/-} 4.27 or Ob-ZSF1-SAR247799, p<0.05 and 57.3 {+/-} 1.82 Le-ZSF1-CTRL), independently of any modification of arterial blood pressure. In old animals, SAR247799 reduced urinary protein/creatinine ratio, an index of glomerular injury, (10.3 {+/-} 0.621 vs 8.17 {+/-} 0.231 for Ob-ZSF1-CTRL vs Ob-ZSF1-SAR247799, respectively, p<0.05 and 0.294 {+/-} 0.029 for Le-ZSF1-CTRL, mean {+/-} SEM) and the fractional excretion of electrolytes. Circulating lymphocytes were not decreased by SAR247799, confirming lack of S1P1 desensitization. ConclusionsThese experimental findings suggest that S1P1 activation with SAR247799 could improve LVH, cardiac diastolic and renal function in HFpEF patients.