Post-Developmental Deletion of Cardiomyocytes PR Domain Containing 16 (prdm16) Causes Pathological Hypertrophy

Despite recent medical advances, heart failure (HF) remains to be the leading cause of mortality worldwide. Delineating the underlying molecular mechanisms involved in the pathogenesis of HF is critical for the development of new therapies. The transcription factor PRDM16 is involved in cell fate determination and differentiation. We previously showed that PRDM16 variants/deletion resulted in left ventricular non-compaction cardiomyopathy in humans and mice indicating its involvement in cardiac development. Here, we investigated the role of PRDM16 in adult cardiac physiology. We showed that patients with HF exhibited a significant reduction in cardiac PRDM16 mRNA expression compared to control individuals. These results were substantiated by the significant attenuation of Prdm16 mRNA 2 weeks post- transverse aortic constriction (TAC) in mice when compared to age matched sham controls. Additionally, cultured neonatal rat ventricular cardiomyocytes treated with the hypertrophy inducing agent, phenylephrine, demonstrated a suppression of Prdm16 gene expression while fibrotic gene expression was elevated. To directly assess the contribution of PRDM16 to cardiac hypertrophy and HF, we generated mice with tamoxifen-inducible cardiomyocyte-specific Prdm16 deletion (CiPrdm16). CiPrdm16 KO mice developed concentric hypertrophy as evidenced by enhanced heart weight/tibia length, elevated left ventricular mass and increased cardiomyocyte hypertrophy. Initially, ciPrdm16 KO mice exhibited enhanced contractility but progressively developed contractile dysfunction and impaired diastolic function. Consistent with these findings, transcriptomic analysis revealed an increase in protein synthesis pathways in ciPrdm16 KO hearts compared to wild-type controls. Collectively, these data show for the first time that PRDM16 transcriptionally regulates pro-hypertrophic signaling in the adult mouse heart and may contribute to the progression of HF in humans.