Clinical science
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We have demonstrated previously that mouse and human islets express ECS (endocannabinoid system) elements, and that short-term activation of islet cannabinoid CB1r and CB2r (cannabinoid type 1 and 2 receptors respectively) stimulates insulin secretion in vitro. There is evidence that the ECS is overactive in Type 2 diabetes, impairing glucose homoeostasis, but little is known about whether it is implicated in islet dysfunction. Therefore the aim of the present study was to investigate the effect of chronic exposure of isolated mouse islets to cannabinoid receptor agonists on islet gene expression and function. ⋯ Neither glucose-stimulated insulin secretion nor acute insulin secretory responses to ACEA or JWH015 at 16 mM glucose were substantially modified by a 48 h or 7 day pre-exposure to these cannabinoid receptor agonists, but the stimulation of secretion at 3 mM glucose by 100 nM ACEA was significantly reduced after prolonged treatment with ACEA. Despite JWH015-induced reductions in islet glucagon content at 48 h and 7 days, there were no reductions in arginine-induced glucagon secretion from islets pre-exposed to JWH015 or ACEA. These data indicate that treatment of islets with agonists of CB1r and CB2r for up to 7 days does not have any major impact on islet function, suggesting that the impairments in glucose homoeostasis observed following overactivation of the ECS should be sought in relation to insulin resistance rather than β-cell dysfunction.
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AT(2)Rs [AngII (angiotensin II) type 2 receptors] contribute to the cardioprotective effects of angiotensin II receptor blockers, possibly via kinins acting on the B(1)R (B(1) receptor) and B(2)R (B(2) receptor). Recent studies have shown that a lack of B(2)R up-regulates B(1)R and AT(2)R; however, the pathophysiological relevance of such an event remains unclear. We hypothesized that up-regulation of AT(2)R and B(1)R compensates for the loss of B(2)R. ⋯ Blockade of AT(2)R or B(1)R worsened cardiac remodelling, hypertrophy and dysfunction associated with increased inflammation and ERK1/2 phosphorylation and decreased NO excretion in B(2)R(-/-) mice, which were exacerbated by dual blockade of B(1)R and AT(2)R. No such effects were seen in WT mice. Our results suggest that, in the absence of B(2)R, both B(1)R and AT(2)R play important compensatory roles in preventing deterioration of cardiac function and remodelling post-MI possibly via suppression of inflammation, TGFβ(1) and ERK1/2 signalling.
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The risk stratification in patients presenting with acute dyspnoea remains a challenge. We therefore conducted a prospective, observational cohort study enrolling 292 patients presenting to the emergency department with acute dyspnoea. A proteomic approach for antibody-free targeted protein quantification based on high-end MS was used to measure LTBP2 [latent TGF (transforming growth factor)-binding protein 2] levels. ⋯ In a multivariate Cox regression analysis, LTBP2 was the strongest independent predictor of death [HR (hazard ratio), 3.76 (95% CI, 2.13-6.64); P<0.0001]. In conclusion, plasma levels of LTBP2 present a novel and powerful predictor of all-cause mortality, and particularly pulmonary death. Cause-specific prediction of death would enable targeted prevention, e.g. with pre-emptive antibiotic therapy.
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ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin II receptor blockers) are already widely used for the treatment and prevention of cardiovascular disease and their potential role in other disease states has become increasingly recognized. COPD (chronic obstructive pulmonary disease) is characterized by pathological inflammatory processes involving the lung parenchyma, airways and vascular bed. ⋯ The review will, in particular, address the emerging evidence that ACE inhibition could have a beneficial effect on skeletal muscle function and cardiovascular co-morbidity in COPD patients. The evidence to support the effect of RAS blockade as a novel therapeutic approach in COPD will be discussed.
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Randomized Controlled Trial
MicroRNA-34a regulates the longevity-associated protein SIRT1 in coronary artery disease: effect of statins on SIRT1 and microRNA-34a expression.
Endothelial senescence is thought to play a role in CAD (coronary artery disease). miR-34a (microRNA-34a) and other SIRT1 (silent information regulator 1)-related miRs have recently been found to target SIRT1 leading to endothelial senescence. In the present study, we investigated whether SIRT1-related miRs, including miR-9, miR-34a, miR-132, miR-181a, miR-195, miR-199a, miR-199b and miR-204, and SIRT1 were expressed in EPCs (endothelial progenitor cells) obtained from patients with CAD, and whether statins (atorvastatin or rosuvastatin) affected these levels. To determine the effects of miR-34a on SIRT1, cultured EPCs transfected with miR-34a were analysed for total SIRT1 protein levels. ⋯ A randomized clinical study has shown that the atorvastatin group had markedly decreased miR-34a levels and increased SIRT1 levels, whereas the rosuvastatin group showed no change in these levels. Levels of other miRs remained unchanged in the atorvastatin and rosuvastatin groups. In conclusion the results of the present study suggest that miR-34a may regulate SIRT1 expression in EPCs and that atorvastatin up-regulates SIRT1 expression via inhibition of miR-34a, possibly contributing to the beneficial effects of atorvastatin on endothelial function in CAD.