Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation

Abstract

Ingle KA, Kain V, Goel M, Prabhu SD, Young ME, Halade GV. Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation. Am J Physiol Heart Circ Physiol 309: H1827-H1836, 2015. First published October 2, 2015; doi:10.1152/ajpheart.00608.2015.-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 cardiomyocytespecific Bmal1 knockout (CBK) mice display early alterations in cardiac diastolic function, extracellular matrix (ECM) remodeling, and inflammation modulators by investigating CBK mice and littermate controls at 8 and 28 wk of age (i.e., prior to overt systolic dysfunction). Left ventricles of CBK mice exhibited (P Ͻ 0.05): 1) progressive abnormal diastolic septal annular wall motion and reduced pulmonary venous flow only at 28 wk of age; 2) progressive worsening of fibrosis in the interstitial and endocardial regions from 8 to 28 wk of age; 3) increased (Ͼ1.5 fold) expression of collagen I and III, as well as the matrix metalloproteinases MMP-9, MMP-13, and MMP-14 at 28 wk of age; 4) increased transcript levels of neutrophil chemotaxis and leukocyte migration genes (Ccl2, Ccl8, Cxcl2, Cxcl1, Cxcr2, Il1␤) with no change in Il-10 and Il-13 genes expression; and 5) decreased levels of 5-LOX, HO-1 and COX-2, enzymes indicating impaired resolution of inflammation. In conclusion, genetic disruption of the cardiomyocyte circadian clock results in diastolic dysfunction, adverse ECM remodeling, and proinflammatory gene expression profiles in the mouse heart, indicating signs of early cardiac aging in CBK mice.aging; Bmal1; circadian clock; extracellular matrix; inflammation; diastolic dysfunction NEW & NOTEWORTHYCardiomyocyte-specific Bmal1 gene deletion in heart progresses to 1) diastolic dysfunction with significant age-dependent hypertrophy; 2) dilative hypertrophy marked with endocardial fibrosis and interstitial fibrosis in an age-dependent manner; and 3) age-dependent ventricular fibrosis displaying aggravated extracellular matrix deposition and defective resolution of the inflammation response.THE CIRCADIAN CLOCK is a timekeeping system that regulates physiological performance and behavior relative to day-night cycles. Oscillations in cardiovascular functions are firmly established, including time-of-day-dependent fluctuations in blood pressure, heart rate, and cardiac output (9, 10, 31). Night shift work and frequent time zone changes result in a dissociation between this intrinsic timekeeping mechanism and the environment, which is associated with increased risk of adverse cardiovascular effects (such as myocardial infarction and sudden cardiac death) (5, 15, 33). In mammals, the timekeeping ...

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