Differential Regulation of MMPs, Apoptosis and Cell Proliferation by the Cannabinoid Receptors CB1 and CB2 in...

Cannabinoids (CB) are implicated in cardiovascular diseases via the two main receptor subtypes CB₁R and CB₂R. This study investigated whether cannabinoids regulate the activity of matrix metalloproteases (MMP-2, MMP-9) in vascular smooth muscle cells (VSMCs) and in cells of cardiac origin (H9c2 cell line). The influence of CB₁- and CB₂ receptor stimulation or inhibition on cell proliferation, apoptosis and glucose uptake was also evaluated. We used four compounds that activate or block CB receptors: arachidonyl-2-chloroethylamide (ACEA)-CB₁R agonist, rimonabant-CB₁R antagonist, John W. Huffman (JWH133)-CB₂R agonist and CB₂R antagonist-6-Iodopravadoline (AM630). Treatment of cells with the CB₂R agonist JWH133 decreased cytokine activated secretion of proMMP-2, MMP-2 and MMP-9, reduced Fas ligand and caspase-3-mediated apoptosis, normalized the expression of TGF-beta1 and prevented cytokine-induced increase in glucose uptake into the cell. CB₁R inhibition with rimonabant showed similar protective properties as the CB₂R agonist JWH133, but to a lesser extent. In conclusion, CB₁R and CB₂R exert opposite effects on cell glucose uptake, proteolysis and apoptosis in both VSMCs and H9c2 cells. The CB₂R agonist JWH133 demonstrated the highest protective properties. These findings may pave the way to a new treatment of cardiovascular diseases, especially those associated with extracellular matrix degradation.