The Sphingosine‐1‐Phosphate Analog, FTY720, Reverses Diastolic Dysfunction and Hypertrophy in Familial Hypertrophic Cardiomyopathy

Abstract

BackgroundHypertrophic cardiomyopathy (HCM) patients present with progressively worsening hypertrophy, diastolic dysfunction and fibrosis, ending in heart failure with preserved ejection fraction. At the molecular level, a common pathology found is an increase in myofilament‐calcium (Ca) sensitivity. Previously, we have shown that oxidative modification of myofilament proteins, as a result of increased oxidative stress in HCM, may be a direct mediator of this increase. FTY720 is an immunomodulating drug, clinically used in the treatment of multiple sclerosis, which we have previously identified to have anti‐fibrotic and anti‐hypertrophic effects in a model of pressure‐overload‐induced hypertrophy. We sought to understand whether agonism of the sphingosine‐1‐phosphate receptor by FTY720 would be of therapeutic benefit in HCM, and its effects on oxidative modification.MethodsWe treated an HCM mouse model linked to a mutation in tropomyosin (Tm‐E180G) and non‐transgenic (NTG) littermates with FTY720 or vehicle for six weeks. We assessed cardiac function and morphology using echocardiography and pressure‐volume (PV) relations and the myofilament‐Ca‐response using detergent‐treated (skinned) fibers. We also investigated if signaling pathways were altered.ResultsWe found that FTY720‐treated Tm‐E180G mice had a significant reduction in left atrial size, E/A and E/Em ratios compared to significantly increased baseline measurements as assessed by echocardiography. PV relations revealed significant improvements in the end‐diastolic pressure volume relationship, preload recruitable stroke work, and relaxation constant (Tau). FTY720‐treated NTG mice displayed a significant decrease in ejection fraction and rate of maximum pressure development in early systole compared to vehicle‐treated NTG mice assessed by PV relations. Skinned fiber bundles revealed a significant decrease in myofilament‐Ca‐responsiveness. We attributed these functional improvements to a down‐regulation of S‐glutathionylation of cardiac myosin binding protein‐C in FTY720‐treated Tm‐E180G mice. The increases in oxidative modification in vehicle treated Tm‐E180G mice were due to an up‐regulation of NADPH oxidase 2 enzyme expression (NOX2), and fibrosis and hypertrophy to increased periostin, TGF‐beta expression, and GATA4 phosphorylation. These maladaptive changes were reversed by FTY720 treatment.ConclusionsIn Tm‐E180G mice, FTY720 improves diastolic function and morphology by reversing oxidative modification of myofilament proteins, resulting in a decrease in myofilament‐Ca‐responsiveness, via down‐regulation of NOX2 and other maladaptive remodeling signals.Support or Funding InformationR01 HL128468 (BMW, RJS) and F31 HL127996 (DMR)