1,721,046 research outputs found
[Metformin and left ventricular remodeling after acute myocardial infarction: molecular mechanisms and clinical implications]
No full textDespite clear advances in reperfusion therapy and pharmacological treatment, a large proportion of patients with an acute myocardial infarction will die of its consequences. In this regard, it is very important to understand the molecular processes underpinning ischemia-reperfusion injury and occurrence of left ventricular dysfunction, with the aim to develop mechanism-based therapeutic strategies. Experimental evidence indicates that metformin, a biguanide often used in the treatment of diabetes, has favorable effects on left ventricular function. This effect is largely mediated by activation of AMP-activated protein kinase (AMPK), a key molecule orchestrating many biochemical processes such as glucose uptake, glycolysis, oxidation of free fatty acids and mitochondrial biogenesis. These processes significantly contribute to raise ATP levels and restore myocardial contractile efficiency. AMPK also activates endothelial nitric oxide synthase and promotes autophagy, thus preventing inflammation and cellular death. These basic studies prompted many researchers to test the cardioprotective effects of metformin in the clinical setting. In diabetic patients with ST-elevation myocardial infarction (STEMI), retrospective analyses showed that metformin is associated with reduced infarct size as compared to non-metformin-based strategies, implicating beneficial effects beyond glucose control. A recent randomized trial, the GIPS-III study, has postulated that metformin may improve left ventricular function following STEMI even in patients without diabetes. Metformin (500 mg twice/day), administered 3h after percutaneous coronary intervention, did not result in improved left ventricular ejection fraction after 4-month follow-up. Based on these results, it remains unclear whether metformin exerts a cardioprotective effect regardless of glycemic control. Further randomized studies in diabetic and nondiabetic patients are required to address these important questions. The present review critically discusses established knowledge and evidence gaps on the effects of metformin on left ventricular function in diabetic and nondiabetic patients with myocardial infarction
Obesity-induced impairment of pluripotent stem cells: novel insights into vascular repair strategies
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Role of oxidative stress in endothelial insulin resistance
No full textThe International Diabetes Federation estimates that 316 million people are currently affected by impaired glucose tolerance (IGT). Most importantly, recent forecasts anticipate a dramatic IGT increase with more that 470 million people affected by the year 2035. Impaired insulin sensitivity is major feature of obesity and diabetes and is strongly linked with adverse cardiometabolic phenotypes. However, the etiologic pathway linking impaired glucose tolerance and cardiovascular disease remains to be deciphered. Although insulin resistance has been attributed to inflammatory programs starting in adipose tissue, emerging evidence indicates that endothelial dysfunction may represent the upstream event preceding peripheral impairment of insulin sensitivity. Indeed, suppression of reactive oxygen species-dependent pathways in the endothelium has shown to restore insulin delivery to peripheral organs by preserving nitric oxide (NO) availability. Here we describe emerging theories concerning endothelial insulin resistance, with particular emphasis on the role oxidative stress. Complex molecular circuits including endothelial nitric oxide synthase, prostacyclin synthase, mitochondrial adaptor p66(Shc), nicotinamide adenine dinucleotide phosphate-oxidase oxidase and nuclear factor kappa-B are discussed. Moreover, the review provides insights on the effectiveness of available compounds (i.e., ruboxistaurin, sildenafil, endothelin receptor antagonists, NO donors) in restoring endothelial insulin signalling. Taken together, these aspects may significantly contribute to design novel therapeutic approaches to restore glucose homeostasis in patients with obesity and diabetes
Ageing, metabolism and cardiovascular disease
No full textAge is one of the major risk factors associated with cardiovascular disease (CVD). About one fifth of the world population will be aged 65 or older by 2030 with an exponential increase in CVD prevalence. It is well established that environmental factors (overnutrition, smoking, pollution, sedentary lifestyles) may lead to premature defects in mitochondrial functionality, insulin signalling, endothelial homeostasis and redox balance fostering early senescent features. Over the last few years, molecular investigations unveiled common signalling networks which may link the aging process with deterioration of cardiovascular homeostasis and metabolic disturbances, namely insulin resistance. These different processes seem to be highly interconnected and their interplay may favour adverse vascular and cardiac phenotypes responsible for myocardial infarction, stroke and heart failure. In the present review, we carefully describe novel molecular cues underpinning aging, metabolism and CVD. In particular, we describe a dynamic interplay between emerging pathways such as FOXOs, AMPK, SIRT1, p66(Shc) , JunD and NF-kB. Such an overview will provide the background for attractive molecular targets to prevent age-driven pathology in the vasculature and the heart. This article is protected by copyright. All rights reserved
Insulin resistance, diabetes, and cardiovascular risk
No full textObesity and type 2 diabetes mellitus (T2DM) are major drivers of cardiovascular disease (CVD). The link between environmental factors, obesity, and dysglycemia indicates that progression to diabetes with time occurs along a "continuum", not necessarily linear, which involves different cellular mechanisms including alterations of insulin signaling, changes in glucose transport, pancreatic beta cell dysfunction, as well as the deregulation of key genes involved in oxidative stress and inflammation. The present review critically addresses key pathophysiological aspects including (i) hyperglycemia and insulin resistance as predictors of CVoutcome, (ii) molecular mechanisms underpinning the progression of diabetic vascular complications despite intensive glycemic control, and (iii) stratification of CV risk, with particular emphasis on emerging biomarkers. Taken together, these important aspects may contribute to the development of promising diagnostic approaches as well as mechanism-based therapeutic strategies to reduce CVD burden in obese and diabetic subjects
P66Shc-induced redox changes drive endothelial insulin resistance
No full textObjective: Obesity-induced insulin resistance (IR) precipitates cardiovascular disease (CVD). Impairment of insulin signalling in the endothelium is emerging as a trigger of IR but the underlying mechanisms remain elusive. The mitochondrial adaptor p66Shc drives endothelial dysfunction via reactive oxygen species (ROS) generation. This study investigates p66Shc role in obesity-induced impairment of endothelial insulin signalling. Methods: All experiments were performed in leptin-deficient (LepOb/Ob) and wild-type (WT) mice. Results: Endothelium-dependent relaxations to insulin were blunted in LepOb/Ob as compared to WT. Interestingly, in vivo gene silencing of p66Shc restored insulin response via IRS-1/Akt/eNOS pathway. Furthermore, p66Shc knockdown in endothelial cells isolated from LepOb/Ob mice attenuated ROS production, free fatty acids (FFA) oxidation and prevented dysregulation of redox-sensitive pathways such as nuclear factor-kappa-B (NF-kB), AGE precursor methylglyoxal and PGI2 synthase. Conclusions: Targeting endothelial p66Shc may represent a promising strategy to prevent IR and CVD in obese individual
Molecular mechanisms of vascular dysfunction and cardiovascular biomarkers in type 2 diabetes
No full textPrevalence of obesity and type 2 diabetes (T2DM) is alarmingly increasing worldwide. Albeit advances in therapy have reduced morbidity and mortality in T2DM, cardiovascular risk is far to be eradicated and mechanism-based therapeutic approaches are in high demand. In this perspective, deciphering novel molecular networks of vascular disease will be instrumental to develop novel diagnostic and therapeutic strategies in people affected by diabetes. There is therefore a need to address current knowledge gaps in disease aetiology in order to support innovation in diagnosis and treatment. Unfortunately, we are still lacking cost-effective markers able to identify atherosclerotic vascular disease at an early stage. The issue of risk stratification deserves attention because not every T2DM patient carries the same degree of inflammation and oxidative stress. The diversity of metabolic phenotypes with different outcomes underscores the need for cardiovascular risk stratification within such heterogeneous population. Early predictors of vascular damage are mandatory to implement intensive treatment strategies and, hence, reduce cardiovascular disease burden in this setting. In this review we critically discuss novel molecular mechanisms of diabetic vascular disease and their possible translation to the clinical setting
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