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

Kevin A Ingle,Vasundhara Kain,Mehak Goel,Martin E Young,Ganesh V Halade,Sumanth D Prabhu

doi:10.1152/ajpheart.00608.2015

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 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 < 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 (>1.5 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, Il1β) 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.

Highlights

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
Cardiomyocyte-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
To determine if CBK mice develop age-dependent changes in LV mass, we measured the weights of the right and left ventricles

Summary

Introduction

Cardiomyocyte-specific Bmal 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 impact of disruption of two main transcription factors, CLOCK and BMAL1, has been investigated [42] These studies reveal important roles for these clock components in the heart at the levels of contractility, electrophysiology, metabolism, signaling, translation, and transcription [7]. Of these models, genetic ablation of BMAL1 in the heart elicits the most striking phenotype from 28 wk onwards: age-onset development of dilated cardiomyopathy associated with reduced life span. With increased ECM deposition, the transforming growth factor (TGF-␤) signaling cascade, including SMAD2 (Mothers against decapentaplegic homolog 2), was activated in CBK hearts by 28 wk of age. Bmal deletion in mice initiated dilative hypertrophy, diastolic dysfunction, and ECM responses and an impaired resolution of

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