Cannabinoid CB1/CB2 Receptors in the Heart: Expression, Regulation, and Function

Abstract

Endocannabinoids exert their actions in the heart and vessels, at least in part, by stimulating the cannabinoid CB and the CB receptor subtypes which belong to a group of seven transmembrane-spanning receptors and are coupled to Gi/o-proteins. Activation of cardiovascular CB receptors leads to depressed cardiac contractility and hypotension. Conversely, in most studies, the CB receptor antagonists are cardioprotective against ischemia reperfusion injury, myocardial ischemia, heart failure, and cardiomyopathies. Evidence to date indicates that CB receptor activation is cardioprotective. CB receptor-mediated effects such as anti-inflammation and anti-fibrosis may be in part opposite to the actions of the CB receptor. The aim of this review is to up-date on recent experimental findings and controversies on the role of endocannabinoid system in the myocardial injury with emphasis on pathophysiological processes such as left ventricular remodeling, cardiac fibrosis, hypertrophy, and endothelial dysfunction. Recent experimental studies employing genetic deficiency of CB and CB receptors and endocannabinoid anandamide metabolizing enzymes are reviewed. Moreover, the protective mechanisms which are mediated by cannabinoid receptors during ischemic preconditioning as well as in the early and late phase after myocardial infarction are discussed in the context of possible therapeutic implications.Keywords: cannabinoid receptors, CB , CB , heart, myocardial infarction, heart remodeling . IntroductionEndocannabinoids, its degrading enzymes and the cannabinoid CB and CB receptors are present in rodent and human cardiovascular tissues. In addition to its role in the control of the central nervous system, the endocannabinoid system ECS may play a pivotal part in cardiovascular regulation by heart diseases reviewed in [ -] .In normal physiological conditions, ECS is not highly regulated. However, by cardiovascular pathologies, this system is activated and may reflect a protective response which limits cardiac injury. Activated ECS has been implicated in acute cardiovascular conditions such as hemorrhagic, septic, and cardiogenic shock as well as in chronic diseases such as coronary heart disease, heart failure, and cardiomyopathy.Endocannabinoids exert their actions in the heart and vessels, at least in part, by stimulating the cannabinoid CB and the CB receptor subtypes which belong to a group of seven transmembrane-spanning receptors and are coupled to Gi/o-proteins [ , ]. Signaling through the CB receptor elicits hypotension, bradycardia, and negative inotropy [ ]. Moreover, this receptor subtype is implicated in inflammation, apoptosis, oxidative stress [ ], and metabolic dysregulation [ ], thereby contributing to tissue injury. The CB receptors, on the contrary, may play a compensatory anti-inflammatory, anti-oxidative, and anti-atherogenic role [ , ] contributing to cardiovascular protection.Nevertheless, the role of cannabinoid receptors in the heart under several pathological conditions remains controversial. ...

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“…The most common reason for this is a build-up of fatty deposits on the inner walls of the blood vessels that supply the heart or brain. Strokes can also be caused by bleeding after myocardial ischaemia [243].…”

“…Since the initial studies performed by Steffens et al in 2005 [254] proving the atheroprotective capacity of the ∆9-THC in mice model via CB2 receptor (Table 3), a great number of studies has been performed [243,255] in experimental animal model (male ApoE-/-mice) in order to study both the CB2 receptor role in the diseases and the atheroprotective capacity of some agonist cannabinoids such as WIN55212-2 [256] (Fig. 6).…”

“…On the one hand, there is an over-production of endocannabinoids contributing to the cardiovascular depressive state associated with these diseases [260]. On the other hand, endocannabinoids have been proposed to protect against myocardial ischemia/reperfusion injury through CB2 receptor in protecting against myocardial, cerebral and hepatic ischemia/reperfusion injury [243,260,261]. The activation of CB2 receptor in injured myocardium produces different protectives responses.…”

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“…CB 2 receptor‐mediated effects such as anti‐inflammation and antifibrosis are also beneficial. To date, little is known about the interaction of the CB 1 /CB 2 receptors with other receptors such as angiotensin‐II receptors (Fulmer, Makenzie, & Thewke, ; Kaschina, ).…”

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“…Como se muestra en la Figura 4, cada receptor posee siete dominios, a pesar de que sólo comparten un 44% de homología en su estructura, se ha visto que tienen una amplia similitud en sus perfiles de ligandos y antagonistas; así también, se ha descrito que existe una similitud del 99.8% entre los CB1 de los roedores y el humano (17). El CB1 es el receptor acoplado a proteína G más abundante en las terminaciones nerviosas excitadoras e inhibitorias pre-sinápticas del cerebro de los mamíferos (18), además se expresa en muchos otros tejidos periféricos, tales como el tejido adiposo (19), hígado (20), el músculo esquelético (21), riñón (22), corazón (23), piel (24) y las células-β del páncreas (25). En contraste, el receptor CB2 se expresa principalmente en las células de los sistemas inmunitario así como el hematopoyético, y en menor medida en órganos, como el hígado, y en células tipo osteoblastos y microglia (26)(27)(28).…”