Aims:
GPR55 is a cannabinoid-sensitive lipid receptor activated amongst others by delta-9-tetrahydrocannabinol and antagonized by cannabidiol. Given the rising popularity of medical and recreational cannabis and cannabidiol consumption, it is mandatory to elucidate the role of GPR55 in cardiovascular physiology and disease. We aimed at characterizing the impact of GPR55 on cardiomyocyte homeostasis and left ventricular (LV) hypertrophy.
Methods and results:
Female and male global GPR55 knock-out (GPR55-/-) and wild-type (WT) mice were characterized after 28-days subcutaneous infusion with angiotensin II (AngII; 1 µg/kg/min) or vehicle. Upon AngII challenge GPR55-/- mice exhibited significantly lower LV expression of pathological hypertrophy markers such as Nppa, Nppb (atrial/brain natriuretic peptide), Myh7 (Myosin heavy chain), connective tissue growth factor (Ctgf), collagens and interleukin (Il) 6 compared to WT despite an evident AngII triggered structural hypertrophic phenotype (n=6-10). This sex-independent alleviation of maladaptive hypertrophy features was further accompanied by promotion of inotropy and preservation of contractile reserve upon sustained AngII treatment. Moreover, GPR55 deficient hearts exhibited an up-regulation of calcium-dependent proteins, such as Calmodulin and Calcineurin, as well as of glucose and fatty acid transporters independent of the AngII challenge. More in-depth analyses of the cardiomyocyte effect of GPR55 deficiency revealed accelerated mitochondrial respiration independent of the given substrate, increased Ca2+ transients and amplitude, with unaltered coupling of calcium release and removal channels and pumps, and accelerated sarcomere contraction/relaxation kinetics. Selective GPR55 blockade with CID16020046 could mimick the GPR55-/- cardiomyocyte phenotype in wild-type (WT) myocytes while not affecting GPR55 deficient cells (n=60-90 cells/2-3 hearts).
Conclusion:
Our study demonstrates GPR55 to be crucially involved in regulation of cardiomyocyte calcium homeostasis, sarcomere function and mitochondrial respiration and identifies GPR55 as a potential target to mitigate maladaptive hypertrophy upon neurohumoral hyperactivation in both, females and males.