Key result
Gpr55 deficiency alleviated maladaptive pro-hypertrophic and inflammatory gene expression and improved inotropy and adrenergic responsiveness compared to wild-type mice, especially in females.
Why the study?
In vitro studies suggest cannabinoid-signalling interferes with cardiomyocyte contractility and hypertrophy, but the in vivo functional contribution of cannabinoid-sensitive receptor GPR55 to cardiomyocyte homeostasis and neurohumorally induced hypertrophy was unknown.
Does Gpr55 deficiency or blockade alter cardiomyocyte homeostasis and counteract angiotensin II-induced maladaptation in mice?
Does Gpr55 deficiency or blockade alter cardiomyocyte homeostasis and counteract angiotensin II-induced maladaptation in mice?
GPR55 deficiency or blockade counteracts angiotensin II-induced maladaptive hypertrophy and improves cardiomyocyte contractility, particularly in females, suggesting GPR55 as a potential therapeutic target.
GPR55 deletion disrupts cardiomyocyte homeostasis and hypertrophy in mice; leaves open its role in human heart failure.
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 Ca 2+ 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 Ca 2+ 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.
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Kohlhaas et al. (2024) studied Cardiomyocyte hypertrophy. Gpr55 deficiency vs. Wild-type (WT) mice was evaluated on Cardiomyocyte hypertrophy, gene expression, inotropy, and adrenergic responsiveness. Gpr55 deficiency alleviated maladaptive pro-hypertrophic and inflammatory gene expression and improved inotropy and adrenergic responsiveness compared to wild-type mice, especially in females.
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