Circadian Governance of Cardiac Growth

Abstract

The cardiomyocyte circadian clock temporally governs fundamental cellular processes, leading to 24-h rhythms in cardiac properties (such as electrophysiology and contractility). The importance of this cell-autonomous clock is underscored by reports that the disruption of the mechanism leads to adverse cardiac remodeling and heart failure. In healthy non-stressed mice, the cardiomyocyte circadian clock modestly augments both cardiac protein synthesis (~14%) and mass (~11%) at the awake-to-sleep transition (relative to their lowest values in the middle of the awake period). However, the increased capacity for cardiac growth at the awake-to-sleep transition exacerbates the responsiveness of the heart to pro-hypertrophic stimuli/stresses (e.g., adrenergic stimulation, nutrients) at this time. The cardiomyocyte circadian clock orchestrates time-of-day-dependent rhythms in cardiac growth through numerous mechanisms. Both ribosomal RNA (e.g., 28S) and the PI3K/AKT/mTOR/S6 signaling axis are circadian regulated, peaking at the awake-to-sleep transition in the heart. Conversely, the negative regulators of translation (including PER2, AMPK, and the integrated stress response) are elevated in the middle of the awake period in a coordinated fashion. We speculate that persistent circadian governance of cardiac growth during non-dipping/nocturnal hypertension, sleep apnea, and/or shift work may exacerbate left ventricular hypertrophy and cardiac disease development, highlighting a need for the advancement of chronotherapeutic interventions.