Role of TRPM4 and Piezo1 ion channels in cardiac mechanotransduction underlying pressure overload-induced left ventricular hypertrophy

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Embargoed until 2023-03-09
Copyright: Guo, Yang
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Abstract
Pathological left ventricular hypertrophy (LVH) induced by mechanical pressure overload is the most powerful independent predictor of cardiac mortality in clinic. Current treatment methods focus on removing the pressure overload stimulus for LVH, which does not reverse adverse cardiac remodelling completely. Importantly, the molecular signalling pathways involved in pressure overload induced-LVH are potential targets for therapeutic intervention. Although numerous molecular signalling steps in the induction of LVH have been identified to date, the initial step when mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling remains unresolved. As the primary molecular transducers of mechanical stimuli that function in the cardiovascular system, several ion channels, including mechanosensitive ones, have been considered as potential contributors to cardiac hypertrophy signalling pathways. The focus of this project is to investigate the role of two types of ion channels, including TRPM4 and Piezo1, in cardiac mechanotransduction underlying pressure overload-induced LVH. By employing wild-type and conditional cardiac gene knockout mouse LVH model based on aortic transverse constriction, this project demonstrates that TRPM4 channel is an important component of the Ca2+-dependent mechanosensory signalling pathway that contributes to LVH in response to pressure overload; selective deletion of TRPM4 channels in mouse cardiomyocytes results in an approximately 50% reduction in pressure overload-induced LVH. Also, this project provides methodological foundation of new in vitro approaches to investigate Piezo1-mediated cardiac mechanotransduction. Chemical agonist-evoked Piezo1 activation and likely isotropic stretch-induced Piezo1 activation were shown in both HL-1 atrial myocyte-like cell line and isolated mouse ventricular cardiomyocytes, visualised by Ca2+ imaging. In addition, the data from this project provide in vitro evidence of the functional interaction between Piezo1 and TRPM4 channels, reflected in altered action potential frequency in HL-1 cells. These findings contribute to better understanding of the mechano-electrochemical transduction which initiates the signalling pathway in pressure overload-induced LVH and thus provide the basis for development of potential novel therapeutic targets for prevention of pathological LVH.
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Publication Year
2022
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Thesis
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PhD Doctorate
UNSW Faculty