Zyxin protects from hypertension-induced cardiac dysfunction

Abstract

Arterial hypertension causes left ventricular hypertrophy leading to dilated cardiomyopathy. Following compensatory cardiomyocyte hypertrophy, cardiac dysfunction develops due to loss of cardiomyocytes preceded or paralleled by cardiac fibrosis. Zyxin acts as a mechanotransducer in vascular cells that may promote cardiomyocyte survival. Here, we analyzed cardiac function during experimental hypertension in zyxin knockout (KO) mice. In zyxin KO mice, made hypertensive by way of deoxycorticosterone acetate (DOCA)-salt treatment telemetry recording showed an attenuated rise in systolic blood pressure. Echocardiography indicated a systolic dysfunction, and isolated working heart measurements showed a decrease in systolic elastance. Hearts from hypertensive zyxin KO mice revealed increased apoptosis, fibrosis and an upregulation of active focal adhesion kinase as well as of integrins α5 and β1. Both interstitial and perivascular fibrosis were even more pronounced in zyxin KO mice exposed to angiotensin II instead of DOCA-salt. Stretched microvascular endothelial cells may release collagen 1α2 and TGF-β, which is characteristic for the transition to an intermediate mesenchymal phenotype, and thus spur the transformation of cardiac fibroblasts to myofibroblasts resulting in excessive scar tissue formation in the heart of hypertensive zyxin KO mice. While zyxin KO mice per se do not reveal a cardiac phenotype, this is unmasked upon induction of hypertension and owing to enhanced cardiomyocyte apoptosis and excessive fibrosis causes cardiac dysfunction. Zyxin may thus be important for the maintenance of cardiac function in spite of hypertension.

Characterisation of Lipoma-Preferred Partner as a Novel Mechanotransducer in Vascular Smooth Muscle Cells

“…Moreover, the difference in the myogenic response between the MA segments isolated from the WT and LPP-KO mice was maintained when these were derived from 6-month-old (6 M) animals made hypertensive for 21 days using the deoxycorticosterone acetate (DOCA)-salt model of hypertension ( Figure 9 f), [ 23 ]. In MA segments isolated from 12-month-old hypertensive LPP-KO mice, the myogenic tone did not differ from the values measured in MA segments isolated from 6-month-old hypertensive LPP-KO mice (cf.…”

The role of zyxin in signal transduction and its relationship with diseases

“…The results indicated that, under high blood pressure conditions, mice with zyxin gene knockout exhibited abnormalities such as impaired cardiac contraction, increased apoptosis, and intensified fibrosis. This research suggests that zyxin plays a crucial role in maintaining heart function under hypertensive conditions ( Al-Hasani et al, 2022 ). These findings reveal the involvement of zyxin in the pathogenesis of cardiac diseases, providing new insights into the mechanisms underlying the development of heart diseases.…”

“…However, no abnormal phenotypes were observed upon zyxin gene knockout in mice ( Hoffman et al, 2003 ), which may be attributed to genetic compensatory mechanisms ( Rossi et al, 2015 ). Although zyxin knockout mice can develop and grow normally ( Hoffman et al, 2003 ), under experimental hypertension conditions, they exhibit more pronounced abnormalities in cardiac contractile function, increased apoptosis, and exacerbated fibrosis compared to wild-type mice ( Nahar, 2017 ; Al-Hasani et al, 2022 ). This indicates the crucial role of zyxin in responding to physiological/pathological stressors, while genetic compensatory mechanisms may mask some effects of zyxin deficiency under normal conditions, necessitating further research for clarification.…”

“…Zyxin plays a regulatory role in cardiomyocytes within the cardiovascular system. Lack of Zyxin may lead to cardiomyocyte apoptosis and excessive fibrosis, promoting myocardial remodeling and affecting heart function ( Nahar, 2017 ; Al-Hasani et al, 2022 ). This suggests that Zyxin could have potential implications in the treatment of cardiovascular diseases, emerging as a novel area for regulating cardiomyocyte function.…”

Cardiovascular Functions of Ena/VASP Proteins: Past, Present and Beyond

“…However, targeting of Ena/VASP proteins to β-cytoplasmic networks by EVH1- or SH3-domain mediated interactions, including αII-spectrin, vinculin, and zyxin is also possible. Interestingly, gene deletion of the latter proteins is also associated with compromised heart development and function [ 190 , 191 , 192 ]. In Mena/VASP double deficient mice, Z-discs appeared wavy and fractured and actin filaments of the I-band appeared disorganized [ 12 ].…”