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bioRxiv · 10.1101/2024.07.07.602358

Unveiling reversibility and plasticity in cardiac hypertrophy: insights from a transverse aortic constriction-release model

Shiraishi, M.
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Abstract

Transverse aortic constriction (TAC) is a well-established animal model used to study the pathomechanisms of pressure overload-induced heart failure. A number of studies have shown that treatment of the heart failure in this model may reverse the associated hypertrophy and fibrosis. However, because no TAC-release model in which hemodynamics improve upon alleviation of the physical stenosis has yet been established, the histologic changes and regulatory molecular biological mechanisms underlying the reversibility of cardiac hypertrophy and fibrosis are unknown. This study was conducted to establish an animal TAC-release model and thereby investigate the mechanisms that govern reversibility and plasticity of myocardial hypertrophy, fibrosis, and angiogenesis. TAC surgery was performed on rats, and 4 weeks later TAC release was achieved by cutting the constricting threads. TAC-subjected heart exhibited severe myocardial hypertrophy, fibrosis, and increased angiogenesis, along with diastolic dysfunction. Heart released from TAC showed reduced hypertrophy and fibrosis and improved diastolic function. Gene expression analysis uncovered regulator of calcineurin 1 (Rcan1) as a key player in cardiac function and histologic changes after TAC release. Rcan1 knockdown exacerbated myocardial hypertrophy and fibrosis in heart released from TAC. The left ventricular afterload relief model revealed that increased oxidative stress and Rcan1 upregulation, which suppresses the calcineurin-NFAT pathway, are key to structural and functional recovery from pressure overload-induced cardiac hypertrophy.

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Shiraishi, M.. 2024-07-07. Unveiling reversibility and plasticity in cardiac hypertrophy: insights from a transverse aortic constriction-release model. https://doi.org/10.1101/2024.07.07.602358

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