Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy

Table 1 Role of cannabinoid agents in diabetes

Cannabinoid agent	Mechanism	Role in diabetes
Anandamide	Endogenous cannabinoid	Elevated in diabetic patients[26]
	CB1 agonist
	CB2 agonist
Rimonabant (SR141716A)	CB1 antagonist	Reduced weight[62]
		Reduced hemoglobin A1c levels[62]
		Reduced fasting blood glucose levels[62]
		Reduced high density lipoprotein, cholesterol and triglyceride levels[62]
		Improved systolic blood pressure[62]
Δ9-tetrahydrocannabinol (THC)	Psychoactive cannabinoid	Lowered blood glucose level[65]; Preserved pancreatic insulin content[65]
	CB1 partial agonist
	CB2 partial agonist
Cannabidiol	Non-psychoactive cannabinoid	Reduced the incidence of type I diabetes[66]
	Low affinity to CB1 and CB2	Immunosuppressive effect[66]

Table 2 Summary of possible mechanisms by which cannabinoids and the endocannabinoid system could modulate diabetic cardiomyopathy

Cannabinoid agent	Mechanism	Effect
Endocannabinoids	Oxidative/Nitrative stress	Influenced ROS and RNS production[28]
	Myocardial remodeling	Triggered activation of signaling pathways (e.g., p38 and JNK-MAPKs), promoting cell death[50,137]
	Inflammation	Increased during inflammation[107]
		Modulating T and B lymphocyte proliferation and apoptosis, inflammatory cytokine production and immune cell activation by inflammatory stimuli[107,108,111]
AM281	Oxidative/Nitrative stress	Attenuated doxorubicin-induced oxidative stress[52]
SR141716A	Oxidative/Nitrative stress	Attenuated doxorubicin-induced oxidative stress[52]
	Inflammation	Reduced plasma levels of the pro-inflammatory cytokines MCP-1 and IL-12 in low density lipoprotein deficient mice[113]
		Inhibited LPS-induced pro-inflammatory IL-6 and TNF-α expression[113]
	Myocardial remodeling	Reduced activation of p38 and JNK/MAPK[90]
		Improved myocardial dysfunction induced in a mouse model of diabetic cardiomyopathy[92]
		Reduced markers of cell death (activated caspase-3 and chromatin fragmentation)[92]
JWH133	Oxidative/Nitrative stress	Reduced ROS release in ApoE knockout mice[54]
	Inflammation	Decreased leukocyte recruitment in ApoE-knockout mice[54]
		Attenuated TNF-α-induced NF-κB activation[116]
		Attenuated ICAM-1 and VCAM-1 up-regulation[116]
Cannabidiol	Oxidative/Nitrative stress	Attenuated oxidative and nitrative stress in the myocardium of streptozotocin-induced diabetic mice[93]
		Prevented changes in markers of lipid peroxidation and oxidative stress in diabetic rats[96]
	Inflammation	Inhibited IκB-α phosphorylation and subsequent p65 NF-κB nuclear translocation[93]
		Attenuated high glucose-induced NF-κB activation in primary human cardiomyocytes[93]
	Myocardial remodeling	Attenuated the established systolic and diastolic dysfunction in diabetic mice[93]
		Attenuated the activation of stress signaling pathways: p38 and JNK/MAPKs[93]
		Enhanced the activity of the pro-survival AKT pathway in diabetic myocardium[93]
		Decreased the activity of the pro-apoptotic enzyme caspase-3[93]
	Autophagy	Promoted endothelial cell survival via HO-1 mediated autophagy[170]
Anandamide	Oxidative/Nitrative stress	Induced NO bioavailability[97]
	Myocardial remodeling	Decrease rat heart mitochondrial O2 consumption[135]
		Increased activation of p38 and JNK/MAPK, followed by cell death[90]
		Enhanced doxorubicin-induced MAPK activation and cell death[90]
Δ9-tetrahydrocannabinol (THC)	Oxidative/Nitrative stress	Regulated redox state in diabetic rats[96]
	Myocardial remodeling	Decreased rat heart mitochondrial O2 consumption[135]
WIN55, 212-2	Inflammation	Reduced atherosclerotic lesion macrophage content and IL-6 and TNF-α levels[114,115]
		Reduced adhesion molecules VCAM-1 and ICAM-1 as well as NF-κB activation[114,115]
HU-308	Inflammation	Attenuated TNF-α-induced NF-κB activation, ICAM-1 and VCAM-1 up-regulation[116]
		Decreased endothelial cell activation and suppression of the acute inflammatory response[56,117]
	Autophagy	Enhanced autophagy levels in heart tissues with diabetic cardiomyopathy[171]
		Increased AMPK phosphorylation while decreasing the phosphorylation of mTOR[171]
HU-210	Myocardial remodeling	Decrease rat heart mitochondrial O2 consumption[135]
		Increased activation of p38 and JNK/MAPK, followed by cell death[90]
		Enhanced doxorubicin-induced MAPK activation and cell death[90]
		Enhanced left ventricular performance in rats with myocardial infarction[143]
AM251	Myocardial remodeling	Improved cardiac function in carbon tetrachloride-induced cirrhosis in rats[140]
		Reduced activation of p38 and JNK/MAPK[90]

LPS: Lipopolysaccharide; AMPK: Adenosine monophosphate activated protein kinase; mTOR: Mammalian target of rapamycin; IL: Interleukin; JNK: Jun N-terminal kinase; MAPK: Mitogen activated protein kinases; TNF-α: Tumor necrosis factor-α; NF-κB: Nuclear factor-kappa B; ICAM-1: Intercellular adhesion molecule-1; VCAM-1: Vascular cell adhesion molecule-1.