Adrenergic receptor blockade-induced regression of pressure-overload cardiac hypertrophy is associated with inhibition of the calcineurin/NFAT3/GATA4 pathway

Abstract

Abstract. calcineurin and its downstream effectors nuclear factor of activated T-cells 3 (nFaT3) and zinc finger-containing transcription factor (GATA4) have been implicated in the development of cardiac hypertrophy. The aims of the present study were to investigate alterations in the calcineurin/NFAT3/GATA4 pathway in pressure-overload hypertrophy, and to determine whether adrenergic receptor blockade affects this signaling pathway. In aorta-banded rats compared with sham-operated rats, a significant increase in the phosphorylation levels of calcineurin and GATA4 was observed (both p<0.05), while the NFAT3 phosphorylation level was markedly decreased (p<0.05). Oral administration of either the non-selective β blocker/α-1 blocker carvedilol or the selective β-1 blocker metoprolol, but not the selective α-1 blocker terazosin, significantly suppressed the activated calcineurin/NFAT3/GATA4 pathway (all p<0.05) in addition to inducing a regression of cardiac hypertrophy. Pressure overload-induced up-regulation of c-myc was markedly attenuated by treatment with either carvedilol or metoprolol (both p<0.05). The present findings may expand our understanding of the correlation between sympathetic activity and the calcineurin/NFAT3/GATA4 pathway, and highlight these signal transducers as effective targets in the management of pressure overload-induced cardiac hypertrophy.

Rosuvastatin prevents pressure overload-induced myocardial hypertrophy via inactivation of the Akt, ERK1/2 and GATA4 signaling pathways in rats

“…In the present study, abdominal aortic constriction-induced pressure overload resulted in left ventricular myocardial hypertrophy due to the increase in LVW/BW, echocardiography characteristics, cardiomyocyte area and mRNA expression levels of the hypertrophy markers ANF and β-MHC. In pressure overload-induced hypertrophic hearts, phosphorylated activation of Akt, ERK1/2 and GATA4 proteins was significantly increased, which was in agreement with the results of previous studies (11,32,33). Briefly, these results showed that the phosphorylation levels of Akt, ERK1/2 and GATA4 proteins are involved in myocardial hypertrophy induced by abdominal aortic constriction.…”

Virtual drug screen reveals context‐dependent inhibition of cardiomyocyte hypertrophy

“…The model is successfully validated in 32 out of 38 (84%) individual hypertrophy experiments, all performed in cardiomyocytes from mice or rats (Alsaad, 2018; Bhavsar et al, 2010; Bombig et al, 1996; Daryadel et al, 2014; Gialama & Maniadakis, 2013; Guan et al, 2019; Lebeche et al, 2001; C. Li et al, 2016; X. Li et al, 2017; Liao et al, 2004; Lin et al, 2015; J. Luo et al, 2016; J.‐D. Luo et al, 2001; Maeno et al, 2000; Morisco et al, 2001; Morishige et al, 2019; Nie et al, 2019; Nkadimeng et al, 2020; Ozakca, 2019; Pacca et al, 2002; Rüdebusch et al, 2022; Samanta et al, 2020; Simpson, 1985; Sysa‐Shah et al, 2012; Takayanagi et al, 2015; Wang, Yao, & Wang, 2010; Yang et al, 2019; Yang et al, 2010; Yin et al, 2016; Yu et al, 2016) (Figure 3a). The model additionally is validated in 28 out of 32 (88%) outcomes from an in vitro drug screen of phenylephrine‐induced cardiomyocyte hypertrophy (Reid et al, 2016) (Figure 3b).…”

“…Li et al, 2017;Liao et al, 2004;Lin et al, 2015;J. Luo et al, 2016 Rüdebusch et al, 2022;Samanta et al, 2020;Simpson, 1985;Sysa-Shah et al, 2012;Takayanagi et al, 2015;Wang, Yao, & Wang, 2010;Yang et al, 2019;Yang et al, 2010;Yin et al, 2016;Yu et al, 2016) (Figure 3a). The model additionally is validated in 28 out of 32 (88%) outcomes from an in vitro drug screen of phenylephrineinduced cardiomyocyte hypertrophy (Reid et al, 2016) (Figure 3b).…”

How does NFAT3 regulate the occurrence of cardiac hypertrophy?

“…NFAT3 is known to be expressed in the heart and has been associated with cardiac hypertrophy [12] . NFAT3 is activated in response to various hypertrophic stimuli, such as mechanical stress [88] and neurohormonal signals [89] . NFAT3 has been implicated in regulating genes that control cell growth [90] , apoptosis [59] , and fibrosis in the heart [91] , all of which are important components of hypertrophic remodelling.…”