Cardiac-specific Suv39h1 knockout ameliorates high-fat diet induced diabetic cardiomyopathy via regulating Hmox1 transcription.

Abstract

Aim: Diabetic Cardiomyopathy (DCM), a common complication of Type 2 Diabetic Mellitus (T2DM), has been emerging as one of the leading causes of mortality in T2DM patients. During the past decade, although, clinical studies concerning DCM are increasing at an exponential rate, mechanisms underlying this disease still can't be clearly defined. Here, we aim to recognize the function of Suv39h1 in DCM and to explore underlying mechanisms during this disease, providing new insights into DCM and novel guide for clinical therapy development.

Materials and methods: We employed cardiac specific Suv39h1 knockout mice to reveal the role of Suv39h1 in high-fat diet induced DCM and using human cardiomyocyte line AC16 cells treated with Suv39h1 siRNA or inhibitor Chaetocin to further explore the mechanism during lipotoxicity condition.

Key findings: Cardiac Suv39h1 knockout ameliorated manifestations of DCM, including cardiac function indexes, cardiomyocyte hypertrophy, interstitial fibrosis, along with improved metabolic disorder in mice. Further, interfering human AC16 cardiomyocytes with siSuv39h1 down-regulated lipotoxicity induced cardiac hypertrophy, inflammation, and fibrosis markers. Subsequent mRNA-seq using siSuv39h1 and SCR AC16 cells discovered a well-recognized cytoprotective, anti-oxidant, and anti-inflammation factor-Hmox1, prominently upregulated in Suv39h1 ablation cells versus SCR under lipotoxicity condition. ChIP assay revealed that Suv39h1 could bind to Hmox1 promoter and reversed by Chaetocin or small interfering RNA.

Significance: These results suggested that the protective effects in DCM rendered by Suv39h1 ablation may work through activating Hmox1 transcription and protein function, providing new insights into pathogenesis of DCM and novel epigenetic target for clinical DCM therapies.