Frontier
Copyright ©The Author(s) 2022.
World J Diabetes. May 15, 2022; 13(5): 387-407
Published online May 15, 2022. doi: 10.4239/wjd.v13.i5.387
Table 2 Summary of possible mechanisms by which cannabinoids and the endocannabinoid system could modulate diabetic cardiomyopathy
Cannabinoid agent
Mechanism
Effect
EndocannabinoidsOxidative/Nitrative stressInfluenced ROS and RNS production[28]
Myocardial remodeling Triggered activation of signaling pathways (e.g., p38 and JNK-MAPKs), promoting cell death[50,137]
InflammationIncreased 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 stressAttenuated doxorubicin-induced oxidative stress[52]
SR141716AOxidative/Nitrative stressAttenuated doxorubicin-induced oxidative stress[52]
InflammationReduced 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 remodelingReduced 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]
JWH133Oxidative/Nitrative stressReduced ROS release in ApoE knockout mice[54]
InflammationDecreased leukocyte recruitment in ApoE-knockout mice[54]
Attenuated TNF-α-induced NF-κB activation[116]
Attenuated ICAM-1 and VCAM-1 up-regulation[116]
CannabidiolOxidative/Nitrative stressAttenuated 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]
InflammationInhibited IκB-α phosphorylation and subsequent p65 NF-κB nuclear translocation[93]
Attenuated high glucose-induced NF-κB activation in primary human cardiomyocytes[93]
Myocardial remodelingAttenuated 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]
AutophagyPromoted endothelial cell survival via HO-1 mediated autophagy[170]
AnandamideOxidative/Nitrative stressInduced 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 stressRegulated redox state in diabetic rats[96]
Myocardial remodeling Decreased rat heart mitochondrial O2 consumption[135]
WIN55, 212-2InflammationReduced 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-308InflammationAttenuated 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]
AutophagyEnhanced autophagy levels in heart tissues with diabetic cardiomyopathy[171]
Increased AMPK phosphorylation while decreasing the phosphorylation of mTOR[171]
HU-210Myocardial 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]
AM251Myocardial remodelingImproved cardiac function in carbon tetrachloride-induced cirrhosis in rats[140]
Reduced activation of p38 and JNK/MAPK[90]