The pathogenesis and clinical features of diabetic cardiomyopathy have been well-studied in the past decade, but effective approaches to prevent and treat this disease are limited. Diabetic ...cardiomyopathy occurs as a result of the dysregulated glucose and lipid metabolism associated with diabetes mellitus, which leads to increased oxidative stress and the activation of multiple inflammatory pathways that mediate cellular and extracellular injury, pathological cardiac remodelling, and diastolic and systolic dysfunction. Preclinical studies in animal models of diabetes have identified multiple intracellular pathways involved in the pathogenesis of diabetic cardiomyopathy and potential cardioprotective strategies to prevent and treat the disease, including antifibrotic agents, anti-inflammatory agents and antioxidants. Some of these interventions have been tested in clinical trials and have shown favourable initial results. In this Review, we discuss the mechanisms underlying the development of diabetic cardiomyopathy and heart failure in type 1 and type 2 diabetes mellitus, and we summarize the evidence from preclinical and clinical studies that might provide guidance for the development of targeted strategies. We also highlight some of the novel pharmacological therapeutic strategies for the treatment and prevention of diabetic cardiomyopathy.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is ubiquitously expressed in most eukaryotic cells and functions to induce a broad range of cellular defenses against exogenous and endogenous ...stresses, including oxidants, xenobiotics, and excessive nutrient/metabolite supply. Because the production and fate of stem cells are often modulated by cellular redox and metabolic homeostasis, important roles of Nrf2 have emerged in the regulation of stem cell quiescence, survival, self-renewal, proliferation, senescence, and differentiation. In a rapidly advancing field, this review summarizes Nrf2 signaling in the context of stem cell state and function and provides a rationale for Nrf2 as a therapeutic target in stem cell-based regenerative medicine.
As a cellular metabolic and stress sensor, the transcription factor Nrf2 is a pivotal regulator of stem cell self-renewal, proliferation, and differentiation.Nrf2 displays cell type-specific and/or stage-dependent impact on stem cell biology in response to various environmental cues.Nrf2 modulates PSCs through the regulation of pluripotency factors, metabolism, redox homeostasis, and cellular stress responses.Nrf2 maintain ASCs self-renewal, quiescence, and regenerative capacity while protecting against ASC depletion in response to stress and aging.
The two major obstacles in the successful transplantation of islets for diabetes treatment are inadequate supply of insulin-producing tissue and immune rejection. Induction of the differentiation of ...human bone marrow-derived mesenchymal stem cells (hMSCs) into insulin-producing cells (IPCs) for autologous transplantation may alleviate those limitations.
hMSCs were isolated and induced to differentiate into IPCs through a three-stage differentiation protocol in a defined media with high glucose, nicotinamide, and exendin-4. The physiological characteristics and functions of IPCs were then evaluated. Next, about 3 × 10(6) differentiated cells were transplanted into the renal sub-capsular space of streptozotocin (STZ)-induced diabetic nude mice. Graft survival and function were assessed by immunohistochemistry, TUNEL staining and measurements of blood glucose levels in the mice.
The differentiated IPCs were characterized by Dithizone (DTZ) positive staining, expression of pancreatic β-cell markers, and human insulin secretion in response to glucose stimulation. Moreover, 43% of the IPCs showed L-type Ca2+ channel activity and similar changes in intracellular Ca2+ in response to glucose stimulation as that seen in pancreatic β-cells in the process of glucose-stimulated insulin secretion. Transplantation of functional IPCs into the renal subcapsular space of STZ-induced diabetic nude mice ameliorated the hyperglycemia. Immunofluorescence staining revealed that transplanted IPCs sustainably expressed insulin, c-peptide, and PDX-1 without apparent apoptosis in vivo.
IPCs derived from hMSCs in vitro can ameliorate STZ-induced diabetic hyperglycemia, which indicates that these hMSCs may be a promising approach to overcome the limitations of islet transplantation.
Endothelial progenitor cells (EPCs) respond to stromal cell-derived factor 1 (SDF-1) through chemokine receptors CXCR7 and CXCR4. Whether SDF-1 receptors involves in diabetes mellitus-induced EPCs ...dysfunction remains unknown.
To determine the role of SDF-1 receptors in diabetic EPCs dysfunction.
CXCR7 expression, but not CXCR4 was reduced in EPCs from
mice, which coincided with impaired tube formation. Knockdown of CXCR7 impaired tube formation of EPCs from normal mice, whereas upregulation of CXCR7 rescued angiogenic function of EPCs from
mice. In normal EPCs treated with oxidized low-density lipoprotein or high glucose also reduced CXCR7 expression, impaired tube formation, and increased oxidative stress and apoptosis. The damaging effects of oxidized low-density lipoprotein or high glucose were markedly reduced by SDF-1 pretreatment in EPCs transduced with CXCR7 lentivirus but not in EPCs transduced with control lentivirus. Most importantly, EPCs transduced with CXCR7 lentivirus were superior to EPCs transduced with control lentivirus for therapy of ischemic limbs in
mice. Mechanistic studies demonstrated that oxidized low-density lipoprotein or high glucose inhibited protein kinase B and glycogen synthase kinase-3β phosphorylation, nuclear export of Fyn and nuclear localization of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), blunting Nrf2 downstream target genes heme oxygenase-1, NAD(P)H dehydrogenase (quinone 1) and catalase, and inducing an increase in EPC oxidative stress. This destructive cascade was blocked by SDF-1 treatment in EPCs transduced with CXCR7 lentivirus. Furthermore, inhibition of phosphatidylinositol 3-kinase/protein kinase B prevented SDF-1/CXCR7-mediated Nrf2 activation and blocked angiogenic repair. Moreover, Nrf2 knockdown almost completely abolished the protective effects of SDF-1/CXCR7 on EPC function in vitro and in vivo.
Elevated expression of CXCR7 enhances EPC resistance to diabetes mellitus-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia. The benefits of CXCR7 are mediated predominantly by a protein kinase B/glycogen synthase kinase-3β/Fyn pathway via increased activity of Nrf2.
Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by sulforaphane (SFN) protects from, and deletion of the Nrf2 gene exaggerates, diabetic cardiomyopathy. Angiotensin II (Ang II) plays ...a critical role in the development of diabetic cardiomyopathy. Therefore, whether SFN prevents Ang II-induced cardiomyopathy through activation of Nrf2 was examined using wild-type, global deletion of Nrf2 gene (Nrf2-KO) and cardiomyocyte-specific overexpression of Nrf2 gene (Nrf2-TG) mice.
Administration of a subpressor dose of Ang II to wild-type mice induced cardiac oxidative stress, inflammation, remodeling and dysfunction, all of which could be prevented by SFN treatment with Nrf2 up-regulation and activation. Nrf2-KO mice are susceptible, and Nrf2-TG mice are resistant, respectively, to Ang II-induced cardiomyopathy. Meanwhile, the ability of SFN to protect against Ang II-induced cardiac damage was lost in Nrf2-KO mice. Up-regulation and activation of Nrf2 by SFN is accompanied by activation of Akt, inhibition of glycogen synthase kinase (GSK)-3β, and accumulation of Fyn in nuclei. In vitro up-regulation of Nrf2 by SFN was abolished and nuclear Fyn accumulation was increased when cardiac cells were exposed to a PI3K inhibitor or GSK-3β-specific activator.
These results suggest that Nrf2 plays a central role in the prevention of Ang II-induced cardiomyopathy, and SFN prevents Ang II-induced cardiomyopathy partially via the Akt/GSK-3β/Fyn-mediated Nrf2 activation.
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•Sulforaphane (SFN) can prevent angiotensin II (AngII) -induced cardiomyopathy.•SFN prevents AngII-induced cardiomyopathy via up-regulating and activating Nrf2.•Cardiac overexpression of Nrf2 prevents Ang II-induced cardiomyopathy.•Up-regulation and activation of Nrf2 by SFN is achieved through the Akt/GSK-3β/Fyn pathway.
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, which may be due to sedentary lifestyles with less physical activity and over nutrition as well as an increase in the aging ...population; however, the contribution of pollutants, environmental chemicals, and nonessential metals to the increased and persistent CVDs needs more attention and investigation. Among environmental contaminant nonessential metals, antimony has been less addressed.
Among environmental contaminant nonessential metals, several metals such as lead, arsenic, and cadmium have been associated with the increased risk of CVDs. Antimony has been less addressed, but its potential link to CVDs is being gradually recognized.
Several epidemiological studies have revealed the significant deleterious effects of antimony on the cardiovascular system in the absence or presence of other nonessential metals. There has been less focus on whether antimony alone can contribute to the pathogenesis of CVDs and the proposed mechanisms of such possible effects. This review addresses this gap in knowledge by presenting the current available evidence that highlights the potential role of antimony in the pathogenesis of CVDs, most likely
antimony-mediated redox dyshomeostasis.
More direct evidence from preclinical and mechanistic studies is urgently needed to evaluate the possible roles of antimony in mitochondrial dysfunction and epigenetic regulation in CVDs.
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Summary
Diabetes mellitus among young patients in Asia is caused by a complex set of factors. Although type 1 diabetes (T1D) remains the most common form of diabetes in children, the recent unabated ...increase in obesity has resulted in the emergence of type 2 diabetes (T2D) as a new type of diabetes among adolescents and young adults. In addition to the typical autoimmune type 1 diabetes (T1aD) and T2D patients, there is a variable incidence of cases of non‐autoimmune types of T1D associated with insulin deficiency (T1bD). Additional forms have been described, including fulminant T1D (FT1D). Although most diagnoses of T1D are classified as T1aD, fulminant T1D exists as a hyper‐acute subtype of T1D that affects older children, without associated autoimmunity. Patient with this rare aetiology of diabetes showed a complete loss of β‐cell secretory capacity without evidence of recovery, necessitating long‐term treatment with insulin. In addition, latent autoimmune diabetes in adults is a form of autoimmune‐mediated diabetes, usually diagnosed during the insulin‐dependent stage that follows a non‐insulin requiring phase, which can be diagnosed earlier based on anti‐islet autoantibody positivity. Some reports discuss T1bD. Others are elaborating on the presence of “atypical T1b diabetes,” such as Flatbush diabetes. The prevalence of diabetes mellitus in young adults continues to rise in Asian populations as T2D increases. With improved characterization of patients with diabetes, the range of diabetic subgroups will become even more diverse in the future. Distinguishing T1D, T2D, and other forms of diabetes in young patients is challenging in Asian populations, as the correct diagnosis is clinically important and has implications for prognosis and management. Despite aetiological heterogeneity in the usual clinical setting, early diagnosis and classification of patients with diabetes relying on clinical grounds as well as measuring islet autoantibodies and fasting plasma C‐peptide could provide a possible viable method to minimize complications.
Recently, the dipeptidyl peptidase‐4 (DPP‐4) inhibitor sitagliptin, a major anti‐hyperglycaemic agent, has received substantial attention as a therapeutic target for cardiovascular diseases via ...enhancing the number of circulating endothelial progenitor cells (EPCs). However, the direct effects of sitagliptin on EPC function remain elusive. In this study, we evaluated the proangiogenic effects of sitagliptin on a diabetic hind limb ischaemia (HLI) model in vivo and on EPC culture in vitro. Treatment of db/db mice with sitagliptin (Januvia) after HLI surgery efficiently enhanced ischaemic angiogenesis and blood perfusion, which was accompanied by significant increases in circulating EPC numbers. EPCs derived from the bone marrow of normal mice were treated with high glucose to mimic diabetic hyperglycaemia. We found that high glucose treatment induced EPC apoptosis and tube formation impairment, which were significantly prevented by sitagliptin pretreatment. A mechanistic study found that high glucose treatment of EPCs induced dramatic increases in oxidative stress and apoptosis; pretreatment of EPCs with sitagliptin significantly attenuated high glucose‐induced apoptosis, tube formation impairment and oxidative stress. Furthermore, we found that sitagliptin restored the basal autophagy of EPCs that was impaired by high glucose via activating the AMP‐activated protein kinase/unc‐51‐like autophagy activating kinase 1 signalling pathway, although an autophagy inhibitor abolished the protective effects of sitagliptin on EPCs. Altogether, the results indicate that sitagliptin‐induced preservation of EPC angiogenic function results in an improvement of diabetic ischaemia angiogenesis and blood perfusion, which are most likely mediated by sitagliptin‐induced prevention of EPC apoptosis via augmenting autophagy.
Cadmium is a hazardous metal with multiple organ toxicity that causes great harm to human health. Cadmium enters the human body through occupational exposure, diet, drinking water, breathing, and ...smoking. Cadmium accumulation in the human body is associated with increased risk of developing obesity, cardiovascular disease, diabetes, and metabolic syndrome (MetS). Cadmium uptake is enhanced during pregnancy and can cross the placenta affecting placental development and function. Subsequently, cadmium can pass to fetus, gathering in multiple organs such as the liver and pancreas. Early-life cadmium exposure can induce hepatic oxidative stress and pancreatic β-cell dysfunction, resulting in insulin resistance and glucose metabolic dyshomeostasis in the offspring. Prenatal exposure to cadmium is also associated with increasing epigenetic effects on the offspring's multi-organ functions. However, whether and how maternal exposure to low-dose cadmium impacts the risks of developing type 2 diabetes (T2D) in the young and/or adult offspring remains unclear. This review collected available data to address the current evidence for the potential role of cadmium exposure, leading to insulin resistance and the development of T2D in offspring. However, this review reveals that underlying mechanisms linking prenatal cadmium exposure during pregnancy with T2D in offspring remain to be adequately investigated.
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Metabolic syndrome (MetS) was developed by the National Cholesterol Education Program Adult Treatment Panel III, identifying adults with at least 3 of 5 cardiometabolic risk factors (hyperglycemia, ...increased central adiposity, elevated triglycerides, decreased high-density lipoprotein cholesterol, and elevated blood pressure) who are at increased risk of diabetes and cardiovascular disease. The constellation of MetS component risk factors has a shared pathophysiology and many common treatment approaches grounded in lifestyle modification. Several attempts have been made to define MetS in the pediatric population. However, in children, the construct is difficult to define and has unclear implications for clinical care. In this Clinical Report, we focus on the importance of screening for and treating the individual risk factor components of MetS. Focusing attention on children with cardiometabolic risk factor clustering is emphasized over the need to define a pediatric MetS.
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