| First Author | Schopohl B | Year | 2025 |
| Journal | Br J Pharmacol | Volume | 182 |
| Issue | 3 | Pages | 670-691 |
| PubMed ID | 39428581 | Mgi Jnum | J:359517 |
| Mgi Id | MGI:7787248 | Doi | 10.1111/bph.17350 |
| Citation | Schopohl B, et al. (2024) Gpr55 deficiency crucially alters cardiomyocyte homeostasis and counteracts angiotensin II induced maladaption in female mice. Br J Pharmacol |
| abstractText | 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.mug.kg(-1) min(-1)) or vehicle infusion. In isolated adult Gpr55(-/-) and WT cardiomyocytes, mitochondrial function was assessed under naive 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. |
