Cannabinoid Receptors in Myocardial Injury: A Brother Born to Rival

Abstract

Cannabinoid receptors typically include type 1 (CB1) and type 2 (CB2), and they have attracted extensive attention in the central nervous system (CNS) and immune system. Due to more in-depth studies in recent years, it has been found that the typical CB1 and CB2 receptors confer functional importance far beyond the CNS and immune system. In particular, many works have reported the critical involvement of the CB1 and CB2 receptors in myocardial injuries. Both pharmacological and genetic approaches have been used for studying CB1 and CB2 functions in these studies, revealing that the brother receptors have many basic differences and sometimes antagonistic functions in a variety of myocardial injuries, despite some sequence or location identity they share. Herein, we introduce the general differences of CB1 and CB2 cannabinoid receptors, and summarize the functional rivalries between the two brother receptors in the setting of myocardial injuries. We point out the importance of individual receptor-based modulation, instead of dual receptor modulators, when treating myocardial injuries.

CB1 Cannabinoid Receptor Signaling and Biased Signaling

“…Further, CB1 activation causes hypotension in healthy individuals, but CB1 antagonism reduced blood pressure in obese and diabetic patients with hypertension [ 54 ]. Similarly, CB1 activation may exacerbate myocardial injury in the context of cardiac pathology [ 55 ]. CB1 can also contribute to diet-induced obesity.…”

Cannabinoid Receptor 2-Centric Molecular Feedback Loop Drives Necroptosis in Diabetic Heart Injuries

“…This is different from our previous publication 17 and might be explained by the functional diversity or rivalry of cannabinoid receptors. [39][40][41] While uncovering the detailed mechanisms underlying CB2R-suppressed necroptosis transcription, we found that CB2R modified the coregulator BACH2. BACH2 is a canonical transcription factor shaping the balance between CD4(+) T-cell subsets in innate immune responses.…”

Activation of cannabinoid receptor 2 attenuates Angiotensin II-induced atrial fibrillation via a potential NOX/CaMKII mechanism

“…In our study, the expression of NOX2 and NOX4 was increased in the Ang II-infused mice, and ox-CaMKII also changed accordingly, resulting in mitochondrial damage; this enhanced oxidative stress and fibrosis and ultimately increased the susceptibility to AF. The ECS is an intricate and heterogeneous signaling network composed of (i) endogenous cannabinoids (eCBs) such as AEA and 2-AG and other cannabimimetic ligands, e.g., oleoylethanolamide and stearoylethanolamine; (ii) metabolic enzymes such as fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) and other enzymes that regulate eCBs; and (iii) the G protein-coupled receptors CB1R and CB2R (6). The interactions among them controls the activity level of the ECS, which plays a vital role in pathophysiology during each stage of life (24).…”

“…It was not until 5 years later that another cannabinoid receptor was found in macrophages of the spleen and named cannabinoid receptor 2 (CB2R). The endogenous ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were discovered in 1992 and 1995 (6). The ECS has been reported to play an important role in the pathogenesis and progression of diseases (7), and pharmacological inhibition of CB1R or activation of CB2R exerts cardioprotective effects (8).…”