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Abstract
Cardiac hypertrophic preconditioning (HP) signifies cardioprotection induced by transient pressure overload to resist hypertrophic effects of subsequently sustained pressure overload. Although it is recently found that inflammation triggers the development of nonischemic cardiomyopathy, whether inflammation plays a role in the antecedent protective effects of HP remains unknown. Caspase-1 is a critical proinflammatory caspase that also induces pyroptosis; thus, we investigated the role of caspase-1 using a unique model of HP in mice subjected longitudinally to 3 days of transverse aortic constriction (TAC 3d), 4 days of de-constriction (De-TAC 4d), and 4 weeks of Re-TAC (Re-TAC 4W). Echocardiography, hemodynamics, histology, PCR, and western blot confirmed preserved cardiac function, alleviated myocardial hypertrophy and fibrosis, and less activated hypertrophic signaling effectors in Re-TAC 4W mice, compared with TAC 4W mice. Mechanistically, caspase-1 and its downstream targets IL-1β and IL-18, but not GSDMD, were less activated in Re-TAC 4W mice. Furthermore, in HP mice with AAV-9-mediated cardiac-specific caspase-1 overexpression, the salutary effects of HP were remarkably abrogated, as evidenced by exacerbated cardiac remodeling, dysfunction, and activation of IL-1β and IL-18. Collectively, this study revealed a previously unrecognized involvement of caspase-1 in cardiac HP by regulation of IL-1β and IL-18 and shed light on caspase-1 as an antecedent indicator and target for cardiac hypertrophy.
Highlights
Pathological cardiac hypertrophy is a compensatory response of the heart challenged with pathological stimuli like pressure overload, valve stenosis, or regurgitation (Nakamura and Sadoshima, 2018; Wu et al, 2020a)
We found that Left ventricular end-systolic pressure (LVESP) increased in both the transverse aortic constriction (TAC) group and hypertrophic preconditioning (HP) group, while the HP group showed a significant reduction in left ventricular end-diastolic pressure (LVEDP) compared with that of the TAC group (Figures 1G,V,W)
We found that caspase-1 overexpression aggravated the activation of IL-1β and IL-18 in Re-TAC 4W mice (Figures 6A,B), recapitulating that HP attenuates cardiac hypertrophy and regresses heart failure through downregulation of the inflammatory cascade of caspase-1
Summary
Pathological cardiac hypertrophy is a compensatory response of the heart challenged with pathological stimuli like pressure overload, valve stenosis, or regurgitation (Nakamura and Sadoshima, 2018; Wu et al, 2020a). While these stimuli persist, cardiac hypertrophy will eventually develop into heart failure (Oka et al, 2014; Li et al, 2018). It is of great importance to explore the endogenous protective pathways to regress heart failure from the onset of cardiac hypertrophy. Caspase-1 Regulates Cardiac HP pressure overload (Heusch, 2015; Wei et al, 2015). HP can help develop new therapy to intervene with cardiac hypertrophy early, its underlying mechanism remains elusive
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