Targeting SRPK3 Attenuates Cardiac Hypertrophy and Heart Failure by Improving Mitochondrial Bioenergetics through mRNA Splicing and Decay.

Pathological cardiac hypertrophy is definitely identified as an adverse deterioration of hemodynamically stressful overload, ultimately heightening risk of sudden death as heart failure (HF) ensues. However, molecular mechanisms underlying cardiac hypertrophy pathogenesis have not been fully described. Herein, we employed targeted genetic approaches and in vivo functional imaging to describe a potent cardiac pro-hypertrophic role of serine arginine protein kinase 3 (SRPK3), one of RNA splicing protein kinases family, which serves as a regulator in pathological hypertrophy and HF. Our study revealed heightened level of SRPK3 in the myocardium of transverse aortic constriction (TAC)-administrated mice and patients who suffer from hypertrophic hearts. Adult mammalian extended expression of Srpk3 in cardiomyocytes (CMs) led to mitochondrial defects and dysfunction, inducing spontaneous concentric hypertrophy and HF, and ultimately premature mortality. Conversely, conditional deletion of Srpk3 in CMs attenuated TAC-induced mitochondrial deficits, consequently ameliorating cardiac hypertrophy and HF. Mechanistically, in canonical splicing regulation, we identified SRPK3- serine/arginine splicing-rich factor 2 (SRSF2)-mediated RNA alternative splicing affecting genes related to mitochondrial function. Also, a noncanonical role of SRPK3 involving binding to RPS3 at Ser149 to destabilize and degrade PGC1α mRNA was unveiled. Using genetically edited human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we also showed that SRPK3-induced dual pathway coordinately resulted in defective mitochondrial biogenesis and bioenergetics, thus triggering pathological cardiac hypertrophy, as evidenced by the SRPK3-induced rewiring of mitochondrial proteome and impaired heart fueling. In preclinical treatment, intravein injection of adeno-associated virus 9-Srpk3 short hairpin RNA attenuated concentric hypertrophy and HF progression in mice. Together, our findings help to elucidate the mechanism of mitochondrial proteome depletion in triggering hypertrophic hearts, establishing SRPK3 suppression as a long-term and improved strategy for treating pathological cardiac hypertrophy and HF.