H2S treatment reverts cardiac hypertrophy and increases SERCA2a activity but does not fully restore cardiac Ca2+ handling in hypertensive rats.

Hydrogen sulfide (H2S) has been proposed to play a cardioprotective role, particularly due to its ability to revert left ventricular hypertrophy (LVH) and mitigate cardiac dysfunction in various cardiomyopathies, including hypertensive heart disease. However, the extent to which cardioprotection by H2S involves improvement in Ca2+ handling remains unclear. Although H2S has been reported to influence the function of key Ca2+ handling proteins, most studies have focused on acute administration of H2S donors in isolated cardiomyocytes, rather than in a therapeutic context. In this study, we used a rat model of hypertension induced by abdominal aortic coarctation (AAC) to evaluate the therapeutic potential of NaHS, an H2S donor, on LVH and Ca2+ handling. After 8 weeks of AAC, hypertensive rats developed moderate LVH, which was accompanied by a reduction in both the amplitude and the rate of rise of systolic Ca2+ transients, as well as a decrease in sarcoplasmic reticulum (SR) Ca2+ load. Despite the reduced SR Ca2+ load, the frequency of diastolic Ca2+ sparks remained high, while the incidence and propagation rate of spontaneous Ca2+ waves significantly increased, suggesting enhanced diastolic SR Ca2+ leak, most likely due to hypersensitivity of ryanodine receptors (RyR2) to Ca2+. On the other hand, NaHS administration during the final 4 weeks of AAC reverted both LVH and hypertension, and increased SR Ca2+ reuptake mediated by the SR Ca2+ ATPase (SERCA2a). However, NaHS treatment failed to restore the amplitude and rate of rise of systolic Ca2+ transients or SR Ca2+ load. Furthermore, SR Ca2+ leak might have worsened, since spontaneous Ca2+ waves increased. In conclusion, NaHS treatment does not appear to normalize all Ca2+ handling properties during hypertensive LVH. On the contrary, NaHS may exert an arrhythmogenic effect, likely due to enhanced SERCA2a activity under conditions of unresolved RyR2 Ca2+ hypersensitivity.