Heart failure and cardiovascular disorders represent the leading cause of death in diabetic patients. Here we present a systematic review of the main mechanisms underlying the development of diabetic cardiomyopathy. We also provide an excursus on the relative contribution of cardiomyocytes, fibroblasts, endothelial and smooth muscle cells to the pathophysiology of heart failure in diabetes. After having described the preclinical tools currently available to dissect the mechanisms of this complex disease, we conclude with a section on the most recent updates of the literature on clinical management.

Heart failure in diabetes.

Rationale: The rennin-angiotensin-aldosterone system (RAAS) plays a critical role in the pathogenesis of diabetic cardiomyopathy, but the role of a member of RAAS, angiotensin IV (Ang IV), in this disease and its underlying mechanism are unclear. This study was aimed to clarify the effects of Ang IV and its downstream mediator forkhead box protein O1 (FoxO1) on diabetic cardiomyopathy.

Methods:In vivo, diabetic mice were treated with low-, medium- and high-dose Ang IV, AT4R antagonist divalinal, FoxO1 inhibitor AS1842856 (AS), or their combinations. In vitro, H9C2 cardiomyocytes and cardiac fibroblasts were treated with different concentrations of glucose, low-, medium- and high-dose Ang IV, divalinal, FoxO1-overexpression plasmid (FoxO1-OE), AS, or their combinations.

Results: Ang IV treatment dose-dependently attenuated left ventricular dysfunction, fibrosis, and myocyte apoptosis in diabetic mice. Besides, enhanced autophagy and FoxO1 protein expression by diabetes were dose-dependently suppressed by Ang IV treatment. However, these cardioprotective effects of Ang IV were completely abolished by divalinal administration. Bioinformatics analysis revealed that the differentially expressed genes were enriched in autophagy, apoptosis, and FoxO signaling pathways among control, diabetes, and diabetes+high-dose Ang IV groups. Similar to Ang IV, AS treatment ameliorated diabetic cardiomyopathy in mice. In vitro, high glucose stimulation increased collagen expression, apoptosis, overactive autophagy flux and FoxO1 nuclear translocation in cardiomyocytes, and upregulated collagen and FoxO1 expression in cardiac fibroblasts, which were substantially attenuated by Ang IV treatment. However, these protective effects of Ang IV were completely blocked by the use of divalinal or FoxO1-OE, and these detrimental effects were reversed by the additional administration of AS.

Conclusions: Ang IV treatment dose-dependently attenuated left ventricular dysfunction and remodeling in a mouse model of diabetic cardiomyopathy, and the mechanisms involved stimulation of AT4R and suppression of FoxO1-mediated fibrosis, apoptosis, and overactive autophagy.

Angiotensin IV attenuates diabetic cardiomyopathy via suppressing FoxO1-induced excessive autophagy, apoptosis and fibrosis.

Diabetes causes lipid peroxide to accumulate within cardiomyocytes. Furthermore, lipid peroxide buildup is a risk factor for ferroptosis. This study is aimed at examining whether curcumin can ameliorate ferroptosis in the treatment of diabetic cardiomyopathy. Hematoxylin and eosin and Masson sections were used to examine the morphology, arrangement, and degree of fibrosis of the myocardium of diabetic rabbit models. The expression levels of nuclear Nrf2, Gpx4, Cox1, and Acsl4 in diabetic animal and cell models were quantitatively analyzed using immunofluorescence and western blotting. Nrf2-overexpression lentivirus vectors were transfected into cardiomyocytes, and the protective effects of curcumin and Nrf2 on cardiomyocytes under high glucose stimulation were assessed using terminal deoxynucleotidyl transferase dUTP nick-end labelling and reactive oxygen species probes. Diabetes was found to disorder myocardial cell arrangement and significantly increase the degree of myocardial fibrosis and collagen expression in myocardial cells. Curcumin treatment can increase nuclear transfer of Nrf2 and the expression of Gpx4 and HO-1, reduce glucose induced myocardial cell damage, and reverse myocardial cell damage caused by the ferroptosis inducer erastin. This study confirmed that curcumin can promote the nuclear translocation of Nrf2, increase the expression of oxidative scavenging factors, such as HO-1, reduce excessive Gpx4 loss, and inhibit glucose-induced ferroptosis in cardiomyocytes. This highlights a potentially new therapeutic route for investigation for the treatment diabetic cardiomyopathy.

/pdf/curcumin-attenuates-ferroptosis-induced-myocardial-injury-in-2vsaxuhk.pdf

Curcumin Attenuates Ferroptosis-Induced Myocardial Injury in Diabetic Cardiomyopathy through the Nrf2 Pathway

FoxO1 inhibition alleviates type 2 diabetes-related diastolic dysfunction by increasing myocardial pyruvate dehydrogenase activity.

As a serious cardiovascular complication, diabetic cardiomyopathy (DCM) refers to diabetes-related changes in myocardial structure and function, which is obviously different from those cardiomyopathy secondary to hypertension, coronary heart disease, and valvular disease. The clinical features of DCM are left ventricular hypertrophy, myocardial fibrosis, and impaired diastolic function. DCM will lead to cardiac dysfunction, eventually progress to cardiac arrhythmia, heart failure, and sudden cardiac death. At present, the pathogenesis of DCM is complex and not fully elucidated, and oxidative stress (OS), inflammatory response, glucolipid metabolism disorder, etc., are considered as the potential pathophysiological mechanisms. As a consequence, there is no specific and effective treatment for DCM. OS refers to the imbalance between reactive oxygen species (ROS) accumulation and scavenging, oxidation, and antioxidants in vivo, which is widely studied in DCM. Numerous studies have pointed out that regulating the OS signaling pathways and reducing the generation and accumulation of ROS are potential directions for the treatment of DCM. This review summarizes the major OS signaling pathways that are related to the pathogenesis of DCM, providing ideas about further research and therapy.

/pdf/oxidative-stress-signaling-mediated-pathogenesis-of-diabetic-1u16gx5n.pdf

Oxidative Stress Signaling Mediated Pathogenesis of Diabetic Cardiomyopathy

Forkhead box protein O1 (FOXO1), a nuclear transcription factor, is preferably activated in the myocardium of diabetic mice. However, its role and mechanism in the development of diabetic cardiomyopathy in non-obese insulin-deficient diabetes are unclear. We hypothesized that cardiac FOXO1 over-activation was attributable to the imbalanced myocardial oxidative metabolism and mitochondrial and cardiac dysfunction in type 1 diabetes. FOXO1-selective inhibitor AS1842856 was administered to streptozotocin-induced diabetic (D) rats, and cardiac functions, mitochondrial enzymes PDK4 and CPT1 and mitochondrial function were assessed. Primary cardiomyocytes isolated from non-diabetic control (C) and D rats were treated with or without 1 µM AS1842856 and underwent Seahorse experiment to determine the effects of glucose, palmitate and pyruvate on cardiomyocyte bioenergetics. The results showed diabetic hearts displayed elevated FOXO1 nuclear translocation, concomitant with cardiac and mitochondrial dysfunction (manifested as elevated mtROS level and reduced mitochondrial membrane potential) and increased cell apoptosis (all P < .05, D vs C). Diabetic myocardium showed impaired glycolysis, glucose oxidation and elevated fatty acid oxidation and enhanced PDK4 and CPT1 expression. AS1842856 attenuated or prevented all these changes except for glycolysis. We concluded that FOXO1 activation, through stimulating PDK4 and CPT1, shifts substrate selection from glucose to fatty acid and causes mitochondrial and cardiac dysfunction.

/pdf/foxo1-contributes-to-diabetic-cardiomyopathy-via-inducing-1fddeddb4y.pdf

FOXO1 contributes to diabetic cardiomyopathy via inducing imbalanced oxidative metabolism in type 1 diabetes

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which has lasted for nearly a year, has made people deeply aware of the strong transmissibility and pathogenicity of SARS-CoV-2 since its outbreak in December 2019. By December 2020, SARS-CoV-2 had infected over 65 million people globally, resulting in more than 1 million deaths. At present, the exact animal origin of SARS-CoV-2 remains unclear and antiviral vaccines are now undergoing clinical trials. Although the social order of human life is gradually returning to normal, new confirmed cases continue to appear worldwide, and the majority of cases are sporadic due to environmental factors and lax self-protective consciousness. This article provides the latest understanding of the epidemiology and risk factors of nosocomial and community transmission of SARS-CoV-2, as well as strategies to diminish the risk of transmission. We believe that our review will help the public correctly understand and cope with SARS-CoV-2.

Review of the risk factors for SARS-CoV-2 transmission

XRCC1 (human X-ray repair complementing defective repair in Chinese hamster cell 1) gene is considered a potentially important gene influencing the risk of hepatocellular carcinoma (HCC). Our analyses detected two allelic variants of XRCC1, c.910A>G and c.1686C>G. We aimed to investigate whether these polymorphisms influence the risk of HCC. The association between the XRCC1 polymorphisms and the risk of HCC was analyzed in 719 patients and 662 controls by polymerase chain reaction-restriction fragment length polymorphism. Our data suggested that the genotypes and alleles of c.910A>G and c.1686C>G polymorphisms were statistically associated with the risk of HCC. For c.910A>G, the GG genotype was associated with increased risk of developing HCC compared with the AA wild genotype (OR = 1.95, 95%CI = 1.40-2.70, P G, the risk of HCC was significantly higher for the GG genotype compared with the CC wild genotype (OR = 1.89, 95%CI = 1.375-2.599, P G and c.1686C>G may contribute to the risk of HCC (G versus A: OR = 1.40, 95%CI = 1.20-1.64, P G and c.1686C>G polymorphisms of XRCC1 are associated with the risk of HCC in the Chinese population.

/pdf/association-study-of-c-910a-g-and-c-1686c-g-polymorphisms-in-4o9rhqd6h7.pdf

Association study of c.910A>G and c.1686C>G polymorphisms in XRCC1 gene with risk of hepatocellular carcinoma in the Chinese population.

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FOXO1 contributes to diabetic cardiomyopathy via inducing imbalanced oxidative metabolism in type 1 diabetes

Review of the risk factors for SARS-CoV-2 transmission

Association study of c.910A>G and c.1686C>G polymorphisms in XRCC1 gene with risk of hepatocellular carcinoma in the Chinese population.