Gpr55 deficiency crucially alters cardiomyocyte homeostasis and counteracts angiotensin II induced maladaption in female mice

Abstract

Background and purpose: Cannabis stimulates several G-protein-coupled-receptors and causes bradycardia and hypotension upon sustained consumption. Moreover, in vitro studies suggest an interference of cannabinoid-signalling with cardiomyocyte contractility and hypertrophy. We aimed at revealing a functional contribution of the cannabinoid-sensitive receptor GPR55 to cardiomyocyte homeostasis and neurohumorally induced hypertrophy in vivo.

Experimental approach: Gpr55^-/- and wild-type (WT) mice were characterized after 28-day angiotensin II (AngII; 1·μg·kg^-1 min^-1) or vehicle infusion. In isolated adult Gpr55^-/- and WT cardiomyocytes, mitochondrial function was assessed under naïve conditions, while cytosolic Ca²⁺ handling was additionally determined following application of the selective GPR55 antagonist CID16020046.

Key results: Gpr55 deficiency did not affect angiotensin II (AngII) mediated hypertrophic growth, yet, especially in females, it alleviated maladaptive pro-hypertrophic and -inflammatory gene expression and improved inotropy and adrenergic responsiveness compared to WT. In-depth analyses implied increased cytosolic Ca²⁺ concentrations and transient amplitudes, and accelerated sarcomere contraction kinetics in Gpr55^-/- myocytes, which could be mimicked by GPR55 blockade with CID16020046 in female WT cells. Moreover, Gpr55 deficiency up-regulated factors involved in glucose and fatty acid transport independent of the AngII challenge, accelerated basal mitochondrial respiration and reduced basal protein kinase (PK) A, G and C activity and phospholemman (PLM) phosphorylation.

Conclusions and implications: Our study suggests GPR55 as crucial regulator of cardiomyocyte hypertrophy and homeostasis presumably by regulating PKC/PKA-PLM and PKG signalling, and identifies the receptor as potential target to counteract maladaptation, adrenergic desensitization and metabolic shifts as unfavourable features of the hypertrophied heart in females.

Keywords: CID16020046; G‐protein coupled receptor GPR55; angiotensin II; cannabinoid receptor; cardiomyocyte homeostasis; hypertrophy.