Endocannabinoids and cannabinoid 1 (CB1) receptors have been implicated in cardiac dysfunction inflammation and cell death associated with various forms of shock heart failure and atherosclerosis in addition to their recognized role in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes. 2 intracellular adhesion molecule 1 and vascular cell adhesion molecule 1) increased expression of CB1 advanced glycation end product (AGE) and angiotensin II type 1 receptors (receptor for advanced glycation end product [RAGE] angiotensin II receptor type 1 [AT1R]) p47(phox) NADPH oxidase subunit β-myosin heavy chain isozyme switch accumulation of AGE fibrosis and decreased expression of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a). Pharmacological inhibition or genetic deletion of CB1 receptors attenuated the diabetes-induced cardiac dysfunction and the above-mentioned pathological alterations. Activation of CB1 receptors by endocannabinoids GDC-0032 may play an important role in the pathogenesis of diabetic cardiomyopathy by facilitating MAPK activation AT1R expression/signaling AGE accumulation oxidative/nitrative stress inflammation and fibrosis. Conversely CB1 receptor inhibition may be beneficial in the treatment of diabetic cardiovascular complications. In diabetic patients cardiovascular complications represent the principal cause of morbidity and mortality. Myocardial left ventricular (LV) dysfunction (both diastolic and later systolic) impartial of atherosclerosis and coronary artery disease has been well documented in both humans and animals (1 2 The mechanisms of diabetic cardiomyopathy are GDC-0032 multifaceted including increased oxidative/nitrosative stress (3-6 ) accumulation of advanced glycation end products (AGEs) (7-9) enhanced receptor for advanced glycation GDC-0032 end product (RAGE) and angiotensin II receptor type 1 (AT1R) signaling (3 7 activation of various proinflammatory and cell death signaling pathways [e.g. poly(ADP-ribose) polymerase (PARP)] mitogen-activated protein kinases (MAPKs) (10 14 coupled with consequent changes in the composition of extracellular matrix with enhanced cardiac fibrosis (13 16 myosin heavy chain (MHC) isoform switch (17) and decreased activity of sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a) (18-20) just to mention a few. Recent preclinical and Mlst8 clinical studies have importantly implicated endocannabinoids (novel lipid mediators) and cannabinoid 1 (CB1) receptors (CB1Rs) in the regulation of food intake energy balance and metabolism (21-23). CB1R inhibition with rimonabant GDC-0032 (SR141716/SR1) demonstrated multiple beneficial effects on metabolic and inflammatory markers both in obese and/or type 2 diabetic patients as well as in various preclinical disease models (21 23 CB1Rs are predominantly expressed in the central nervous system (21) but are also present in cardiovascular and virtually all other peripheral tissues albeit at much lower levels (24 25 In the cardiovascular system CB1 activation by endocannabinoids or synthetic ligands leads to complex cardiovascular depressive effects implicated in the cardiovascular collapse associated with various forms of shock (21) and heart failure (26-28). CB1R activation in coronary artery endothelial cells (29) cardiomyocytes (26 27 and inflammatory cells (28 30 mediates MAPK activation reactive oxygen species (ROS) generation and inflammatory response promoting atherosclerosis (31) and cardiac dysfunction (27 28 Furthermore elevated endocannabinoid plasma levels have recently been associated with coronary circulatory dysfunction in human obesity (32) and CB1R blockade or its genetic deletion attenuated proteinuria and/or vascular inflammation and cell death in experimental models of type 1 diabetic nephropathy (33) and/or retinopathy (34). Beneficial effect of CB1 blockade has also been reported in rodent models of type 1 diabetic neuropathy and in various high glucose-induced in vitro experimental paradigms (rev. in 35). In this study we investigated the potential role of the endocannabinoids and CB1R in the pathogenesis of type 1 diabetic cardiomyopathy using selective CB1R inhibitors or CB1 knockout mice. Our results demonstrate that pharmacological inhibition or genetic deletion of CB1 attenuates cardiac dysfunction oxidative stress inflammation and fibrosis in.