Cardiac Gq Receptors and Calcineurin Activation Are Not Required for the Hypertrophic Response to Mechanical Left Ventricular Pressure Overload.

Ze-Yan Yu,Jianxin Wu,Diane Fatkin,Hutao Gong,Scott H Kesteven,Yun Dai,Robert M Graham,Michael P Feneley,Boris Martinac

doi:10.3389/fcell.2021.639509

Abstract

RationaleGq-coupled receptors are thought to play a critical role in the induction of left ventricular hypertrophy (LVH) secondary to pressure overload, although mechano-sensitive channel activation by a variety of mechanisms has also been proposed, and the relative importance of calcineurin- and calmodulin kinase II (CaMKII)-dependent hypertrophic pathways remains controversial.ObjectiveTo determine the mechanisms regulating the induction of LVH in response to mechanical pressure overload.Methods and ResultsTransgenic mice with cardiac-targeted inhibition of Gq-coupled receptors (GqI mice) and their non-transgenic littermates (NTL) were subjected to neurohumoral stimulation (continuous, subcutaneous angiotensin II (AngII) infusion for 14 days) or mechanical pressure overload (transverse aortic arch constriction (TAC) for 21 days) to induce LVH. Candidate signaling pathway activation was examined. As expected, LVH observed in NTL mice with AngII infusion was attenuated in heterozygous (GqI+/–) mice and absent in homozygous (GqI–/–) mice. In contrast, LVH due to TAC was unaltered by either heterozygous or homozygous Gq inhibition. Gene expression of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and α-skeletal actin (α-SA) was increased 48 h after AngII infusion or TAC in NTL mice; in GqI mice, the increases in ANP, BNP and α-SA in response to AngII were completely absent, as expected, but all three increased after TAC. Increased nuclear translocation of nuclear factor of activated T-cells c4 (NFATc4), indicating calcineurin pathway activation, occurred in NTL mice with AngII infusion but not TAC, and was prevented in GqI mice infused with AngII. Nuclear and cytoplasmic CaMKIIδ levels increased in both NTL and GqI mice after TAC but not AngII infusion, with increased cytoplasmic phospho- and total histone deacetylase 4 (HDAC4) and increased nuclear myocyte enhancer factor 2 (MEF2) levels.ConclusionCardiac Gq receptors and calcineurin activation are required for neurohumorally mediated LVH but not for LVH induced by mechanical pressure overload (TAC). Rather, TAC-induced LVH is associated with activation of the CaMKII-HDAC4-MEF2 pathway.

Highlights

Pathological left ventricular hypertrophy (LVH) is the single strongest predictor of cardiovascular mortality and heart failure (Levy et al, 1990; Mudd and Kass, 2008), stimulating extensive research efforts to identify the molecular signaling pathways responsible for its induction as potential therapeutic targets (Mudd and Kass, 2008; Tamargo and Lopez-Sendon, 2011)
We examined the role of cardiac Gq receptors in the induction of LVH in response to either angiotensin II (AngII) infusion or transverse aortic arch constriction (TAC) in transgenic (GqI+/− and GqI−/−) and non-transgenic littermate (NTL) mice
The degree of LVH induced by AngII was significantly reduced in GqI+/− mice (19% and 17% increases in left ventricular weight normalized to body weight (LVW/body weight (BW)) and left ventricular weight normalized to tibia length (LVW/tibial length (TL)), respectively, p < 0.001), and LVH was prevented in GqI−/− mice (Figure 1A)

Summary

Introduction

Pathological left ventricular hypertrophy (LVH) is the single strongest predictor of cardiovascular mortality and heart failure (Levy et al, 1990; Mudd and Kass, 2008), stimulating extensive research efforts to identify the molecular signaling pathways responsible for its induction as potential therapeutic targets (Mudd and Kass, 2008; Tamargo and Lopez-Sendon, 2011). Activation of calcium-calmodulin dependent kinase II (CaMKII) phosphorylates histone deacetylase 4 (HDAC4), promoting its nuclear export and relieving its inhibition of the critical nuclear transcriptional regulator, myocyte enhancer factor 2 (MEF2), enhancing hypertrophic gene transcription (Passier et al, 2000; Backs et al, 2006, 2009) Both the calcineurin-NFAT and the CaMKII-HDAC-MEF2 pathways have been claimed to be both sufficient and necessary for the induction of pathological LVH, not without considerable controversy (Ding et al, 1999; Zhang et al, 1999, 2003, 2005, 2007; Molkentin, 2000, 2013; Zou et al, 2001; Frey and Olson, 2003; Ling et al, 2009). The question of the relative importance of calcineurin and CaMKII activation in pathological hypertrophy remains

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