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Hyperglycemia and insulin resistance are key players in the development of atherosclerosis and its complications. A large body of evidence suggest that metabolic abnormalities cause overproduction of reactive oxygen species (ROS). In turn, ROS, via endothelial dysfunction and inflammation, play a major role in precipitating diabetic vascular disease. A better understanding of ROS-generating pathways may provide the basis to develop novel therapeutic strategies against vascular complications in this setting. Part I of this review will focus on the most current advances in the pathophysiological mechanisms of vascular disease: (i) emerging role of endothelium in obesity-induced insulin resistance; (ii) hyperglycemia-dependent microRNAs deregulation and impairment of vascular repair capacities; (iii) alterations of coagulation, platelet reactivity, and microparticle release; (iv) epigenetic-driven transcription of ROS-generating and proinflammatory genes. Taken together these novel insights point to the development of mechanism-based therapeutic strategies as a promising option to prevent cardiovascular complications in diabetes.

Age 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 have unveiled common signalling networks which may link the ageing 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 ageing, metabolism and CVD. In particular, we describe a dynamic interplay between emerging pathways such as FOXOs, AMPK, SIRT1, p66Shc, JunD and NF‐kB. This overview will provide the background for attractive molecular targets to prevent age‐driven pathology in the vasculature and the heart.

Rationale: Hyperglycemic memory may explain why intensive glucose control has failed to improve cardiovascular outcomes in patients with diabetes. Indeed, hyperglycemia promotes vascular dysfunction even after glucose normalization. However, the molecular mechanisms of this phenomenon remain to be elucidated.Objective: The present study investigated the role of mitochondrial adaptor p66 Shc in this setting. Methods and Results:In human aortic endothelial cells (HAECs) exposed to high glucose and aortas of diabetic mice, activation of p66Shc by protein kinase C ␤II (PKC␤II) persisted after returning to normoglycemia. Persistent p66Shc upregulation and mitochondrial translocation were associated with continued reactive oxygen species (ROS) production, reduced nitric oxide bioavailability, and apoptosis. We show that p66Shc gene overexpression was epigenetically regulated by promoter CpG hypomethylation and general control nonderepressible 5-induced histone 3 acetylation. Furthermore, p66Shc -derived ROS production maintained PKC␤II upregulation and PKC␤II-dependent inhibitory phosphorylation of endothelial nitric oxide synthase at Thr-495, leading to a detrimental vicious cycle despite restoration of normoglycemia. Moreover, p66Shc activation accounted for the persistent elevation of the advanced glycated end product precursor methylglyoxal. In vitro and in vivo gene silencing of p66Shc , performed at the time of glucose normalization, blunted ROS production, restored endothelium-dependent vasorelaxation, and attenuated apoptosis by limiting cytochrome c release, caspase 3 activity, and cleavage of poly (ADP-ribose) polymerase. Conclusions: p66Shc is the key effector driving vascular hyperglycemic memory in diabetes. Our study provides molecular insights for the progression of diabetic vascular complications despite glycemic control and may help to define novel therapeutic targets. (Circ Res. 2012;111:278-289.) Key Words: vascular disease Ⅲ diabetes mellitus Ⅲ free radicals Ⅲ endothelium T he prevalence of diabetes has dramatically increased worldwide, with a further rise anticipated in the next decades. 1,2 Morbidity and mortality from cardiovascular disease is 2-to 8-fold higher in subjects with than in those without diabetes. 3 Editorial, see p 262Recent prospective clinical trials have failed to confirm unequivocal benefits from normalization of glycemia on cardiovascular outcomes. 4 -8 In these trials, intensive glucoselowering therapy was started after a median duration of diabetes ranging from 8 to 11 years. 4 -8 By contrast, early treatment of hyperglycemia reduces the risk of myocardial infarction, diabetes-related deaths, and all-cause mortality. 9 -11 These observations support the concept that hyperglycemic environment may be remembered in the vasculature. 12 Reactive oxygen species (ROS) are probably involved in this phenomenon defined "hyperglycemic memory," but the underlying molecular mechanisms remain unknown. [13][14][15] Overproduction of ROS by mitochondria is considered as a causal link betwe...