Endocannabinoids and cardiovascular prevention: real progress?

The prevalence of obesity continues to increase and represents one of the principal causes of cardiovascular morbidity and mortality. After the discovery of a specific receptor of the psychoactive principle of marijuana, the cannabinoid receptors and their endogenous ligands, several studies have demonstrated the role of this system in the control of food intake and energy balance and its overactivity in obesity. Recent studies with the CB1 receptor antagonist rimonabant have demonstrated favorable effects such as a reduction in body weight and waist circumference and an improvement in metabolic factors (cholesterol, triglycerides, glycemia etc). Therefore, the antagonism of the endocannabinoid (EC) system, if recent data can be confirmed, could be a new treatment target for high risk overweight or obese patients. Obesity is a growing problem that has epidemic proportions worldwide and is associated with an increased risk of premature death (1–3). Individuals with a central deposition of fats have elevated cardiovascular morbidity and mortality (including stroke, heart failure and myocardial infarction) and, because of a growing prevalence not only in adults but also in adolescents, it was reclassified in AHA guidelines as a “major modifiable risk factor” for coronary heart disease (4, 5). Although first choice therapy in obesity is based on correcting lifestyle (diet and physical activity) in patients with abdominal obesity and high cardiovascular risk and diabetes, often it is necessary to use drugs which reduce the risks. The EC system represents a new target for weight control and the improvement of lipid and glycemic metabolism (6, 7)

Assenza di effetti del diabete mellito sull’efficacia e tollerabilità della terapia beta bloccante nei pazienti con insufficienza cardiaca cronica.

10nonenoneMETRA M; NODARI S; DEI CAS A; BIGOTTI T; GNESIN P; VIZZARDI E; FOSCHINI A; TRUSSARDI E; PARRINELLO G; DEI CAS LMetra, Marco; Nodari, Savina; DEI CAS, A; Bigotti, T; Gnesin, P; Vizzardi, Enrico; Foschini, A; Trussardi, E; Parrinello, G; DEI CAS, Livi

Mechanical forces and TGF{beta}1 reduce podocyte adhesion through {alpha}3{beta}1 integrin downregulation

BACKGROUND: Podocyturia is a marker of diabetic nephr- opathy, a possible determinant of its progression and a powerful risk factor for cardiovascular disease. A reduction in podocyte adhesion to the glomerular basement membrane (GBM) via downregulation of alpha3beta1 integrin expression, the main podocyte anchoring dimer to the GBM, may represent one of the mechanisms of podocyturia in glomerular disease. This study investigated the role of mechanical forces and transforming growth factor beta1 (TGFbeta1) in podocyte adhesion and integrin expression. METHODS: Conditionally immortalized murine podocytes were exposed to mechanical stretch and/or TGFbeta1 for 48 h. Podocyte adhesion, apoptosis and alpha3beta1 integrin expression were assessed. RESULTS: Stretch and TGFbeta1 significantly reduced podocyte adhesion and alpha3beta1 integrin expression, events paralleled by increased apoptosis. Blockade of beta1 integrin, with a specific antibody, demonstrated a reduced podocyte adhesion indicating that beta1 integrin downregulation was required for the loss of podocyte adhesion. This was linked to an increase in podocyte apoptosis. The role of apoptosis in podocyte adhesion was further investigated using caspase-3 inhibitors. Podocyte apoptosis inhibition did not affect stretch- and TGFbeta1-mediated integrin downregulation and the loss of podocyte adhesion, suggesting that alpha3beta1 integrin downregulation is sufficient to alter cell adhesion. Although stretch significantly increased podocyte TGFbeta type I, II and III receptors but not podocyte TGFbeta1 secretion, the combination of stretch and TGFbeta1 did not show any additive or synergistic effects on podocyte adhesion and alpha3beta1 integrin expression. CONCLUSIONS: These results suggest that downregulation of alpha3beta1 integrin expression, by mechanical forces or TGFbeta1, is per se sufficient to reduce podocyte adhesion. Apoptosis may represent a parallel important determinant of the podocyte loss from the GBM

Evidence for early impairment of glucagon-like peptide 1-induced insulin secretion in human type 2 (non insulin-dependent) diabetes

To investigate a possible role of an enteroinsular axis involvement in the pathogenesis of type 2 diabetes, plasma glucagon-like peptide 1 (GLP-1) 7-36 amide response to nutrient ingestion was evaluated in type 2 diabetics affected by different degrees of beta-cell dysfunction. METHODS: 14 patients on oral hypoglycaemic treatment (group A: HbA1C = 8.1 +/- 1.8 %) and 11 age-matched diabetic patients on diet only (group B: HbA1C = 6.4 +/- 0.9) participated in the study. 10 healthy volunteers were studied as controls. In the postabsorptive state, a mixed meal (700 kCal) was administered to all subjects, and blood samples were regularly collected up to 180' for plasma glucose, insulin, glucagon, and GLP-1 determination. RESULTS: In the control group, the test meal induced a significant increase in plasma GLP-1 at 30' and 60' (p < 0.01); the peptide concentrations then returning toward basal levels. beta-cell function estimation by HOMA score confirmed a more advanced involvement in group A than in group B (p < 0.01). In contrast, the insulin resistance degree showed a similar result in the two groups (HOMA-R). In group A, first-phase postprandial insulin secretion (0 - 60') resulted, as expected, in being significantly reduced compared to healthy subjects (p < 0.001). In the same patients the mean fasting GLP-1 value was similar to controls, but the meal failed to increase plasma peptide levels, which even tended to decrease during the test (p < 0.01). In group B, food-mediated early insulin secretion was higher than in group A (p < 0.001), although significantly reduced when compared to controls (p < 0.01). Like group A, no GLP-1 response to food ingestion occurred in group B patients in spite of maintained basal peptide secretion. Whereas the test-meal did not significantly modify plasma glucagon levels in the control group, glucagon concentrations increased at 30' and 60' in both diabetic groups (p < 0.01). CONCLUSIONS: 1) The functional integrity of GLP-1 cells results as being seriously impaired even in the condition of mild diabetes; 2) the early peptide failure could contribute to the development of beta-cell deterioration which characterizes overt type 2 diabetes