Disrupting the key circadian regulator CLOCK leads to age-dependent cardiovascular disease

Abstract

The circadian mechanism underlies daily rhythms in cardiovascular physiology and rhythm disruption is a major risk factor for heart disease and worse outcomes. However, the role of circadian rhythms is generally clinically unappreciated. Clock is a core component of the circadian mechanism and here we examine the role of Clock as a vital determinant of cardiac physiology and pathophysiology in aging. Clock mice develop age-dependent increases in heart weight, hypertrophy, dilation, impaired contractility, and reduced myogenic responsiveness. Young Clock hearts express dysregulated mRNAs and miRNAs in the PTEN-AKT signal pathways important for cardiac hypertrophy. We found a rhythm in the Pten gene and PTEN protein in WT hearts; rhythmic oscillations are lost in Clock hearts. Changes in PTEN are associated with reduced AKT activation and changes in downstream mediators GSK-3β, PRAS40, and S6K1. Cardiomyocyte cultures confirm that Clock regulates the AKT signalling pathways crucial for cardiac hypertrophy. In old Clock mice cardiac AKT, GSK3β, S6K1 phosphorylation are increased, consistent with the development of age-dependent cardiac hypertrophy. Lastly, we show that pharmacological modulation of the circadian mechanism with the REV-ERB agonist SR9009 reduces AKT activation and heart weight in old WT mice. Furthermore, SR9009 attenuates cardiac hypertrophy in mice subjected to transverse aortic constriction (TAC), supporting that the circadian mechanism plays an important role in regulating cardiac growth. These findings demonstrate a crucial role for Clock in growth and renewal; disrupting Clock leads to age-dependent cardiomyopathy. Pharmacological targeting of the circadian mechanism provides a new opportunity for treating heart disease.

Drosophila Voltage-Gated Calcium Channel α1-Subunits Regulate Cardiac Function in the Aging Heart

“…Another interesting observation was a slight increase in EDD in wild-type flies at week 3 but not that prominent in Ca 2+ channel mutants, specifically D-type. Our observations are in agreement with earlier published data in mice 60 , 61 and human beings 62 where an increase in EDD is reported with age. Lack of increase in EDD for Ca 2+ channel mutants could point to abnormal cell development due to abnormal Ca 2+ flux which is governed by VGCCs in cardiomyocytes.…”

“…However, D-type flies could not recover revealing a detrimental role of the absence of α1D in cardiac dysfunction. These inferences are in agreement with earlier findings 61 that lack of Ca 2+ influx from Ca v 1 channels leads to diastolic dysfunction. During aging, action potential, transient increase in cytosolic Ca 2+ , and rate of contraction is prolonged which consequently prolong systole and diastole events in the heart 69 , 70 , consistent with the lower maximal heart rate seen in older individuals even during exercise.…”

BMAL1 regulates mitochondrial fission and mitophagy through mitochondrial protein BNIP3 and is critical in the development of dilated cardiomyopathy

“…© The Author(s) 2020 Protein & Cell contractility, and reduced myogenic responsiveness (Alibhai et al, 2017). And, Clock specific mutant in cardiomyocytes resulted in myocardial contractile dysfunction and bradycardia .…”

REV-ERBα ameliorates heart failure through transcription repression

“…These features suggest that REV-ERBα may be a unique "brake" of aberrantly activated gene programs in the disease state through multiple TFs in a tissue-specific manner. However, REV-ERBα's role in the heart remains poorly understood, with one recent report indicating that synthetic agonists can attenuate cardiac hypertrophy (7). The role of REV-ERBα in clinically relevant models of HF and the molecular basis for its actions remain unknown.…”