anandamide and Ventricular-Dysfunction--Left

Ischemic heart disease is associated with inflammation, interstitial fibrosis and ventricular dysfunction prior to the development of heart failure. Endocannabinoids and the cannabinoid receptor CB2 have been claimed to be involved, but their potential role in cardioprotection is not well understood. We therefore explored the role of the cannabinoid receptor CB2 during the initial phase of ischemic cardiomyopathy development prior to the onset of ventricular dysfunction or infarction. Wild type and CB2-deficient mice underwent daily brief, repetitive ischemia and reperfusion (I/R) episodes leading to ischemic cardiomyopathy. The relevance of the endocannabinoid-CB2 receptor axis was underscored by the finding that CB2 was upregulated in ischemic wild type cardiomyocytes and that anandamide level was transiently increased during I/R. CB2-deficient mice showed an increased rate of apoptosis, irreversible loss of cardiomyocytes and persistent left ventricular dysfunction 60 days after the injury, whereas wild type mice presented neither morphological nor functional defects. These defects were due to lack of cardiomyocyte protection mechanisms, as CB2-deficient hearts were in contrast to controls unable to induce switch in myosin heavy chain isoforms, antioxidative enzymes and chemokine CCL2 during repetitive I/R. In addition, a prolonged inflammatory response and adverse myocardial remodeling were found in CB2-deficient hearts because of postponed activation of the M2a macrophage subpopulation. Therefore, the endocannabinoid-CB2 receptor axis plays a key role in cardioprotection during the initial phase of ischemic cardiomyopathy development.

Topics: Animals; Apoptosis; Arachidonic Acids; Cardiomyopathies; Disease Models, Animal; Endocannabinoids; Female; Macrophage Activation; Macrophages; Male; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB2; Signal Transduction; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

The exercise pressor reflex (EPR) is an important neural mechanism that controls blood pressure and heart rate during static muscle contraction. It has been previously demonstrated that the EPR is exaggerated in cardiomyopathy. Both mechanically (group III) and metabolically (group IV) sensitive afferent neurons are important to this reflex in normal humans and animals. In cardiomyopathy, however, the metabolically sensitive afferents are less responsive to activation whereas the mechanically sensitive fibres are overactive. We have demonstrated that this overactivity is responsible for the exaggeration in the EPR. Of importance, we have also demonstrated that the reduced responsiveness in the group IV afferent neuron is an initiating factor in the development of the exaggerated EPR. To date, the mechanism mediating this reduced group IV responsiveness remains unclear. Given that group IV afferent neurons are activated via chemically sensitive receptors, it is logical to suggest that changes in receptor function are responsible for the blunted behaviour of group IV neurons in cardiomyopathy. In order to test this postulate, however, potential receptor candidates must first be identified. The transient receptor potential vanilloid 1 (TRPv1) receptor is a non-selective cation channel that serves as a marker of the group IV afferent neurons in the periphery. We have demonstrated that the TRPv1 is abnormal in cardiomyopathy. It has been shown that the TRPv1 receptor is colocalized with the cannabinoid 1 (CB(1)) receptor on group IV afferent neurons. Therefore, we hypothesized that the function of CB(1) receptors is abnormal in cardiomyopathy. We explored this possibility by using anandamide (AEA), an endogenously produced cannabinoid that has been shown to control blood pressure via activation of the CB(1) receptor. In these studies, we evaluated the cardiovascular responses to intra-arterial injection of AEA into the hindlimb of normal, cardiomyopathic and neonatally capsaicin-treated (NNCAP) rats (rats that lack group IV afferent neurons) to determine whether administration of AEA results in abnormal responses of group IV afferent neurons in cardiomyopathic rats. We determined that AEA controls changes in blood pressure, predominately via activation of the CB(1) receptor in this preparation. We further observed that the blood pressure response to AEA is blunted in cardiomyopathic rats when compared to normal rats. We also observed a reduced blood pressure r

Topics: Animals; Apoptosis; Arachidonic Acids; Blood Pressure; Cannabinoid Receptor Modulators; Capsaicin; Cardiomyopathy, Dilated; Disease Models, Animal; Endocannabinoids; Ganglia, Spinal; Male; Neurons, Afferent; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Sensory System Agents; TRPV Cation Channels; Ventricular Dysfunction, Left

Recent studies have uncovered important cross talk between inflammation, generation of reactive oxygen and nitrogen species, and lipid metabolism in the pathogenesis of cardiovascular aging. Inhibition of the endocannabinoid anandamide metabolizing enzyme, the fatty acid amide hydrolase (FAAH), is emerging as a promising novel approach for the treatment of various inflammatory disorders. In this study, we have investigated the age-associated decline of cardiac function and changes in inflammatory gene expression, nitrative stress, and apoptosis in FAAH knockout (FAAH(-/-)) mice and their wild-type (FAAH(+/+)) littermates. Additionally, we have explored the effects of anandamide on TNF-alpha-induced ICAM-1 and VCAM-1 expression and monocyte-endothelial adhesion in human coronary artery endothelial cells (HCAECs). There was no difference in the cardiac function (measured by the pressure-volume conductance catheter system) between 2- to 3-mo-old (young) FAAH(-/-) and FAAH(+/+) mice. In contrast, the aging-associated decline in cardiac function and increased myocardial gene expression of TNF-alpha, gp91phox, matrix metalloproteinase (MMP)-2, MMP-9, caspase-3 and caspase-9, myocardial inducible nitric oxide synthase protein expression, nitrotyrosine formation, poly (ADP-ribose)polymerase cleavage and caspase-3/9 activity, observed in 28- to 31-mo-old (aging) FAAH(+/+) mice, were largely attenuated in knockouts. There was no difference in the myocardial cannabinoid CB(1) and CB(2) receptor gene expression between young and aging FAAH(-/-) and FAAH(+/+) mice. Anandamide dose dependently attenuated the TNF-alpha-induced ICAM-1 and VCAM-1 expression, NF-kappaB activation in HCAECs, and the adhesion of monocytes to HCAECs in a CB(1)- and CB(2)-dependent manner. These findings suggest that pharmacological inhibition of FAAH may represent a novel protective strategy against chronic inflammation, oxidative/nitrative stress, and apoptosis associated with cardiovascular aging and atherosclerosis.

Topics: Aging; Amidohydrolases; Animals; Apoptosis; Arachidonic Acids; Cell Adhesion; Cells, Cultured; Coronary Vessels; Endocannabinoids; Endothelial Cells; Gene Expression Regulation; Humans; Inflammation; Intercellular Adhesion Molecule-1; Mice; Mice, Knockout; Monocytes; Myocardium; NF-kappa B; Polyunsaturated Alkamides; Reactive Nitrogen Species; Receptors, Cannabinoid; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Ventricular Dysfunction, Left