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Review
. 2021 Sep 17;14(9):936.
doi: 10.3390/ph14090936.

The Endocannabinoid System and Cannabidiol: Past, Present, and Prospective for Cardiovascular Diseases

Martina Rabino  1 , Sara Mallia  1 , Elisa Castiglioni  1 , Davide Rovina  1 , Giulio Pompilio  1   2   3 , Aoife Gowran  1
Affiliations
Review

The Endocannabinoid System and Cannabidiol: Past, Present, and Prospective for Cardiovascular Diseases

Martina Rabino et al. Pharmaceuticals (Basel). .

Abstract

In the past, cannabis was commonly associated with mysticism and illegality. Fortunately, in recent years perspectives and discourses have changed. More prominence has been given to the rigorous scientific effort that led to the discovery of cannabis' many physiological actions and endogenous signalling mechanisms. The endocannabinoid system is a complex and heterogeneous pro-homeostatic network comprising different receptors with several endogenous ligands, numerous metabolic enzymes and regulatory proteins. Therefore, it is not surprising that alterations and dysfunctions of the endocannabinoid system are observed in almost every category of disease. Such high degree of pathophysiological involvement suggests the endocannabinoid system is a promising therapeutic _target and prompted the translation of resurgent scientific findings into clinical therapies. Shifting attitudes toward cannabis also raised other matters such as increased patient awareness, prescription requests, self-medication, recreational use, recognition of new knowledge gaps, renewed scientific activity, and seemingly exponential growth of the cannabis industry. This review, following a general overview of cannabis and the endocannabinoid system, assiduously describes its role within the context of cardiovascular diseases, paying particular attention to the Janus influence that endocannabinoid system modulators can have on the cardiovascular system.

Keywords: cannabinoid receptors; cardiomyopathy; endocannabinoid system; endocannabinoids; phyto-cannabinoids; synthetic cannabinoids.

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Conflict of interest statement

Giulio Pompilio is Chief Scientific Officer of Oloker Therapeutics S.r.l.

Figures

Figure 1
Figure 1
A schematic summary of the main endocannabinoid metabolic pathways. The biosynthesis of the two most researched eCBs, arachidonoyl ethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), starts with the catabolism of phospholipid precursors via the action of two respective enzymes, namely, NAPE phospholipase D (NAPE-PLD) and the alpha or beta isoform of diacylglycerol lipase (DAGL). Despite AEA and 2-AG both possessing an AA chain structural motif, their catabolic pathways are different, and thus are respectively catabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) to form arachidonic acid (AA) and ethanolamine following AEA degradation, or AA and glycerol in the case of 2-AG breakdown. Both products are rapidly re-incorporated into membrane phospholipids. Blue arrows signify enzymatic reactions; black arrow indicates the passage of ions through the ion channel; ↑ i[Ca2+] represents elevated intracellular calcium.
Figure 2
Figure 2
Contribution of the endocannabinoid system (ECS) to cardiovascular pathophysiology and cardioprotection. Schematic representation of the known interaction between the ECS and the bone marrow niche, immune cells, and other cells or cellular cargo that mediate pathophysiological mechanisms in CVDs, e.g., mesenchymal stem cells (MSCs), haematopoietic stem cells (HSCs), adipocytes, and extracellular vesicles (EVs). Comprehensive understanding of the dynamic alterations in the ECS during damage to the myocardium represents a crucial point to establish novel cannabinoid-based therapeutic approaches. For instance, during injury or pathological conditions the ECS becomes dysfunctional and loses specificity of activity that can further drive pathological events. Alterations including increased CB1 expression and anandamide (AEA) during these states activate various molecular signalling such as inflammation and fibrotic signalling. Thus _targeting the ECS by inhibiting or enhancing relevant components, e.g., receptors, eCB metabolism etc., could be of potential benefit to improve current and future treatment strategies aimed at cardioprotection.
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