oa Editorial [Hot Topic: Diabetes Cardiovascular Complications (Guest Editor: Costanza Emanueli)]

Diabetes epidemic represents one of the major threats to the health and life of contemporary people as well as to the budget of the national health systems in both the developed and developing countries. Diabetes is a metabolic disease. Nonetheless, it is equally often considered a cardiovascular pathology, owing to its prevalent association with cardiovascular morbidity and mortality. In fact, in diabetic people, cardiovascular events are not only more frequent but they also result in more severe outcomes [1]. Although these facts are generally accepted, a more systematic characterization of the vicious diabetes attack to the heart and the vessels in various bodily districts and the molecular and cellular mechanisms underpinning these are only partially accomplished. Moreover, the majority of research focuses on the most notorious targets, including large vessels, the kidneys and they eyes. In this thematic issue, a series of seven excellent review articles target cardiovascular complications of diabetes from several complementary focuses. We start with the definition of recently described epigenetic mechanisms, which endure on the vascular chromatin under diabetic conditions [2]. Epigenetics is emerging as a fundamental area of basic and translational research. It represents a phenomenon of altered gene expression without changes in DNA sequence and which is heritable from mother cells to daughter cells and sometimes from parents to off-springs. Epigenetic modifications are mainly mediated by DNA methylation and histone modifications affecting the chromatin status and hence gene transcription. Epigenetics controls embryonic development, as it guides stem cell differentiation and cell lineage specification. Moreover, epigenetics is heavily involved in pathologies such as cancers and, as discussed here, diabetes. In fact, here, we detail how diabetes-induced epigenetic changes can affect gene expression in vascular cells and ensure a long-term memory, whereby epigenetic changes are maintained even long after restoring normo-glycaemic conditions [2]. Abdominal obesity is a major risk factor for both type 2 diabetes and cardiovascular disease. This is in part explained by the fact that the adipose tissue produces adipokines that regulate carbohydrate and lipid metabolism [3]. Adipokines include hormones, inflammatory cytokines and other proteins. Obesity and particularly visceral fat accumulation contributes to impaired insulin sensitivity and atherosclerosis, including through dysregulated production of adipokines [4]. In fact, in obesity, adipose tissue becomes dysfunctional, thus overproducing proinflammatory adipokines, while decreasing the production of beneficial adipokines, including adiponectin [5]. In their review for EMID-DT, Kishida and colleagues focus on adiponectin and illustrate the evidences suggesting that increase in visceral fat brings over hypoadiponectinemia, which in turn contributes to diabetes and atherosclerosis. They also present evidence of how positive changes in life style (proper sleep, nutrition and exercise), body weight loss and medications may increase circulating adiponectin levels and consequently help preventing diabetes and atherosclerosis [4]. Diabetes (both type 1 and type 2) targets the heart not only through contributing into coronary artery disease, but also and often independently by inducing a specific cardiomyopathy characterized by microangiopathy and deposition of interstitial fibrosis, which further limits myocardial perfusion. The overall results are alterations in systolic and diastolic function and ultimately heart failure [6-8]. It has been recently shown that diabetes brings over low or dysfunctional HDL, which in turn alters glucose metabolism. Hence, the existence of a vicious circle emerges. Here, Spillmann and colleagues give an overview of the influence of hyperglycemia, hyperinsulinemia, and dyslipidemia on diabetic cardiomyopathy. Moreover, they report the metabolic features and pleiotropic effects of HDL and explain how HDL could protect the diabetic heart [9]. It is well known that diabetic patients are more susceptible to stroke and that they are more prone to stroke-induced death or severe disabilities. Here, Ergul et al. illustrate the mechanisms and consequences of diabetes-induced cerebrovascular damage, focusing on the role of diabetes-induced brain microvascular disease in stroke pathogenesis and outcome [10]. One possible mechanistic explanation of increased number and severity of cardiovascular events in diabetic people is the diabetes-induced impairment of the cellular machinery, which contributes to tissue protection and repair. In their review, Mangialardi and colleagues focus on post-ischemic vascular regeneration in diabetes. Cumulative evidences suggest the contribution of heart- and/or vessel-resident progenitor cells in post-ischemic angiogenesis and blood flow recovery. In addition, a wide spectrum of inflammatory and/or proangiogenic cells is actively released from the bone marrow and recruited by the ischemic tissue to contribute into its healing. Diabetes severely affects the structure of the bone marrow, by inducing bone marrow microangiopathy [11]. This is associated with an altered stem and progenitor cells compartmentalization in the bone marrow endosteal and vascular niches, which result in changes in hematopoietic progenitor cell egression from the bone marrow and homing at sites of ischemic injury [1,11].....