Cardiomyocyte Specific Bmal1 Deletion Triggers Extracellular Matrix Response Associated with Markers of Impaired Inflammation Resolution and Diastolic Dysfunction

Abstract

The mammalian circadian clock consists of multiple transcriptional regulators that coordinate biological processes in a time‐of‐day‐dependent manner. Cardiomyocyte‐specific deletion of the circadian clock component BMAL1 (aryl hydrocarbon receptor nuclear translocator‐like protein 1) leads to age‐dependent dilated cardiomyopathy and decreased lifespan in mice. We investigated whether cardiomyocyte‐specific BMAL1 knockout (CBK) mice display early alterations in extracellular matrix (ECM) remodeling, inflammation modulators, and cardiac diastolic function. By 28 weeks of age, CBK mice developed diastolic dysfunction, ventricular hypertrophy, increased fibrosis and expression of ECM‐regulatory genes, as well as a gene expression pattern consistent with impaired resolution of inflammation (compared to aged matched controls). More specifically, CBK mice exhibited (p<0.05): 1) increased fibrosis in the interstitial and endocardial regions; 2) increased (>1.5 fold) expression of collagen I and III, as well as the matrix metalloproteinases MMP‐9, MMP‐13, MMP‐14; 3) increased transcript levels of neutrophil chemotaxis and leukocyte migrationgenes (Ccl2, Cxcl2, Cxcl1, Cxcr2); and 4) decreased levels of 5‐LOX, HO‐1 and COX‐2, enzymes that promote the resolution of inflammation. In conclusion, genetic disruption of the cardiomyocyte circadian clock results in ECM remodeling, pro‐inflammatory gene expression profiles, and diastolic dysfunction.