Diabetic Cardiovascular Complications Research Articles

Cell-based therapy for diabetic cardiovascular complications: Prospects and challenges.

Diabetes mellitus is a long-term metabolic condition characterized by high blood glucose levels. This disorder is closely associated with a range of complications affecting small and large blood vessels, including conditions like retinopathy, nephropathy and neuropathy, as well as ischaemic heart disease, peripheral vascular disease and cerebrovascular disease. These complications cause organ and tissue damage in an estimated 33% to 50% of individuals with diabetes. The management of these complications in patients with diabetes is confronted with significant clinical challenges. Present treatment modalities for cardiovascular complications secondary to diabetes are limited and exhibit suboptimal efficacy. Cell-based therapies has shown great promise in regenerative medicine and improving cardiovascular function in individuals with diabetic complications, attributed to their potential for multilineage differentiation and regenerative capacity. In this review, we focus on diabetic cardiovascular complications and provide a brief introduction to the application of cell-based therapies, including the use of stem cells and progenitor cells, their mechanisms of action and the prospects and challenges.

Role of Apigenin in Rats with Type 1 Diabetic Complications

Abstract Background and Aim The main factor contributing to diabetes morbidity and mortality is cardiovascular problems. Apigenin, a naturally occurring flavonoid with anti-inflammatory and anti-diabetic characteristics, was investigated for its cardioprotective potential. Methods Type 1 diabetes model was induced using single injection of streptozotocin and diabetic rats were injected with apigenin. ECG recording and measurement of blood pressure were performed. Biochemical analyses of serum glucose, lipid profile, and creatine kinase were done. Histological examination of cardiac tissues was also performed. Results Diabetic rats had higher levels of glucose and creatine kinase, and impaired lipid profile as compared to the control group. Apigenin improved glycemic control, dyslipidemia, and cardiac function markers. Diabetic group had significantly higher blood pressure values as compared to the control group. The mean systolic and diastolic blood pressure levels dropped after apigenin treatment. ECG showed decrease in heart rate and increase in R-voltage after apigenin-injection as compared to diabetic rats. Moreover, apigenin-injection resulted in reduced histological changes of cardiac tissues compared to diabetic rats. Conclusion Apigenin could serve as potential therapeutic agent to reverse effects of hyperglycemia and its cardiovascular complications in diabetes.

Identification of hub genes associated with diabetic cardiomyopathy using integrated bioinformatics analysis

Diabetic cardiomyopathy (DCM) is a common cardiovascular complication of diabetes, which may threaten the quality of life and shorten life expectancy in the diabetic population. However, the molecular mechanisms underlying the diabetes cardiomyopathy are not fully elucidated. We analyzed two datasets from Gene Expression Omnibus (GEO). Differentially expressed and weighted gene correlation network analysis (WGCNA) was used to screen key genes and molecules. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein–protein interaction (PPI) network analysis were constructed to identify hub genes. The diagnostic value of the hub gene was evaluated using the receiver operating characteristic (ROC). Quantitative real-time PCR (RT-qPCR) was used to validate the hub genes. A total of 13 differentially co-expressed modules were selected by WGCNA and differential expression analysis. KEGG and GO analysis showed these DEGs were mainly enriched in lipid metabolism and myocardial hypertrophy pathway, cytomembrane, and mitochondrion. As a result, six genes were identified as hub genes. Finally, five genes (Pdk4, Lipe, Serpine1, Igf1r, and Bcl2l1) were found significantly changed in both the validation dataset and experimental mice with DCM. In conclusion, the present study identified five genes that may help provide novel targets for diagnosing and treating DCM.

A CEBPB/miR-32–5p/GATA6 axis promotes vascular calcification in type 2 diabetes

Vascular calcification in diabetes patients is a major independent risk factor for developing diabetic cardiovascular complications. However, the mechanisms by which diabetes leads to vascular calcification are complex and not yet fully understood. Our previous study revealed that miR-32–5p is a potential new diagnostic marker for coronary artery calcification. In this study, we found that miR-32–5p levels were significantly greater in the plasma of type 2 diabetes patients with coronary artery calcification and were positively correlated with the coronary artery calcification score. In type 2 diabetic mice, miR-32–5p levels were also elevated in the aorta, and knockout of miR-32–5p inhibited the osteogenic differentiation of vascular smooth muscle cells in vivo. Furthermore, overexpression of miR-32–5p promoted vascular smooth muscle cell calcification, while antagonism of miR-32–5p inhibited vascular smooth muscle cell calcification under high-glucose conditions. GATA binding protein 6 (GATA6) was identified as the key target gene through which miR-32–5p promotes vascular smooth muscle cell calcification. Overexpression of GATA6 antagonized the effects of miR-32–5p on vascular calcification. Additionally, high glucose levels were shown to induce the upregulation of miR-32–5p by activating CCAAT/enhancer binding protein beta (CEBPB). These results suggest that miR-32–5p is an important procalcification factor in vascular calcification associated with type 2 diabetes and identify the CEBPB/miR-32–5p/GATA6 axis as a potential biomarker and therapeutic target for preventing and treating vascular calcification in type 2 diabetes.

Social and Structural Determinants of Cardiovascular Complications of Diabetes.

Cardiovascular disease (CVD) is the leading cause of mortality in people who have diabetes. Racial and ethnic minorities with diabetes have suboptimal management of cardiovascular risk factors, leading to higher mortality. Social and structural determinants of health are external factors that influence an individual's ability to choose positive health behaviors. In this review, we will discuss cardiovascular complications in people who have diabetes and their relationship to social determinants of health (SDOH). Recent innovations in diabetes treatment, including new devices and medications, have improved care and survival. However, disparities in the availability of these treatments to racial and ethnic minorities may contribute to continued inequities in CVD outcomes. Racial/ethnic disparities in CVD relate to inequities in economic opportunity, education and health literacy, neighborhoods and social cohesion, and health care access and quality driven by structural racism.

MiRNA-221 and -222 increase in exosomes upon insulin stimulation of human vascular smooth muscle cells lacking the insulin-like growth factor 1 receptor

As a result of increased vascular inflammation, patients with Type 2 diabetes experience a near 4-fold increase in their risk for heart attack and stroke. miR-221 and -222 are two microRNAs that are upregulated in the vasculature of Type 2 diabetic patients. miR-221/222 act by downregulating the cyclin-dependent kinase inhibitor, p27Kip1, in vascular smooth muscle cells (VSMCs) and exosome-mediated proinflammatory effects on endothelial cells and macrophages. Loss of the insulin-like growth factor receptor (IGFR) in VSMCs can unmask the insulin receptor (IR) and increase insulin signaling. We have demonstrated that the loss of IGFR, coupled with physiological insulin stimulation, promotes an increased expression of miR-221/-222 in murine VSMCs. Respectively, miR-221/222 content in VSMC-derived exosomes increases and p27Kip1 mRNA expression decreases in VSMCs. We asked whether the effect of loss of IGFR in human coronary artery smooth muscle cells (HCASMCs) would also lead to an increase in miR-221/-222 content of VSMC-derived exosomes. Transfection with a CRISPR-cas9 plasmid targeting IGFR resulted in a 50% decrease in IGFR mRNA in HCASMCs, when compared to transfection with negative control CRISPR plasmids. Droplet digital PCR was used to measure expression of miR-221 and miR-222 in the exosomes derived from both sets of HCASMCs. There was no change in the miR-221/222 content of exosomes derived from HCASMCs transfected with the negative control CRISPR following stimulation with 1nM insulin (7.27± 4.75 vs. 11.33 ± 1.09 copies of miR-221 and 6.43 ± 0.43 vs. 4.68 ± 0.02 copies of miR-222). In contrast, there was a 2 to 3-fold increase in miR-221/222 content in exosomes that were derived from HCASMCs with IGFR knockdown following stimulation with 1nM insulin (14.96 ± 0.3 vs. 35.66 ± 3.08 copies of miR-221 and 9.12 ± 1.19 vs.15.44 ± 5.36 copies of miR-222). We conclude that loss of IGFR coupled with physiological insulin stimulation increases the miR-221/222 content of exosomes of HCASMCs, recapitulating the effects of IGFR loss seen in murine VSMCs as well as the effects of diabetes on VSMCs. This model system will allow additional studies connecting the loss of IGFR to the cardiovascular complications of diabetes. Tulane University School of Medicine, Biomedical Sciences Program. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

BAG3 promotes proliferation and migration of arterial smooth muscle cells by regulating STAT3 phosphorylation in diabetic vascular remodeling

BackgroundDiabetic vascular remodeling is the most important pathological basis of diabetic cardiovascular complications. The accumulation of advanced glycation end products (AGEs) caused by elevated blood glucose promotes the proliferation and migration of vascular smooth muscle cells (VSMCs), leading to arterial wall thickening and ultimately vascular remodeling. Therefore, the excessive proliferation and migration of VSMCs is considered as an important therapeutic target for vascular remodeling in diabetes mellitus. However, due to the lack of breakthrough in experiments, there is currently no effective treatment for the excessive proliferation and migration of VSMCs in diabetic patients. Bcl-2-associated athanogene 3 (BAG3) protein is a multifunctional protein highly expressed in skeletal muscle and myocardium. Previous research has confirmed that BAG3 can not only regulate cell survival and apoptosis, but also affect cell proliferation and migration. Since the excessive proliferation and migration of VSMCs is an important pathogenesis of vascular remodeling in diabetes, the role of BAG3 in the excessive proliferation and migration of VSMCs and its molecular mechanism deserve further investigation.MethodsIn this study, BAG3 gene was manipulated in smooth muscle to acquire SM22αCre; BAG3FL/FL mice and streptozotocin (STZ) was used to simulate diabetes. Expression of proteins and aortic thickness of mice were detected by immunofluorescence, ultrasound and hematoxylin-eosin (HE) staining. Using human aorta smooth muscle cell line (HASMC), cell viability was measured by CCK-8 and proliferation was measured by colony formation experiment. Migration was detected by transwell, scratch experiments and Phalloidin staining. Western Blot was used to detect protein expression and Co-Immunoprecipitation (Co-IP) was used to detect protein interaction.ResultsIn diabetic vascular remodeling, AGEs could promote the interaction between BAG3 and signal transducer and activator of transcription 3 (STAT3), leading to the enhanced interaction between STAT3 and Janus kinase 2 (JAK2) and reduced interaction between STAT3 and extracellular signal-regulated kinase 1/2 (ERK1/2), resulting in accumulated p-STAT3(705) and reduced p-STAT3(727). Subsequently, the expression of matrix metallopeptidase 2 (MMP2) is upregulated, thus promoting the migration of VSMCs.ConclusionsBAG3 upregulates the expression of MMP2 by increasing p-STAT3(705) and decreasing p-STAT3(727) levels, thereby promoting vascular remodeling in diabetes. This provides a new orientation for the prevention and treatment of diabetic vascular remodeling.

Regulatory role of peroxynitrite in advanced glycation end products mediated diabetic cardiovascular complications.

The Advanced Glycation End Products (AGE) binding with its receptor can increase reactive oxygen species (ROS) generation through specific signaling mediators. The effect of superoxide (O2-) and O2- mediated ROS and reactive nitrogen species depends on their concentration and location of formation. Nitric oxide (NO) has anti-inflammatory and anticoagulant properties and a vasodilation effect, but NO can be deactivated by reacting with O2-. This reaction between NO and O2- produces the potent oxidant ONOO-. Therefore, ONOO-'s regulatory role in AGEs in diabetic cardiovascular complications must considered as a regulator of cardiovascular complications in diabetes.

Small dense low density lipoprotein predominance in patients with type 2 diabetes mellitus using Mendelian randomization.

Patients with T2DM often suffer from CVD-related complications, significantly impacting morbidity and mortality rates. The upsurge in CVD prevalence among them is partly linked to sd LDL particles. Understanding the mechanisms behind elevated sd LDL levels is critical for preventing and managing cardiovascular complications in diabetes. MR was employed to identify instrumental variables and establish causality, exploring underlying mechanisms. Notably, T2DM itself, insulin resistance, and fasting glucose seemingly do not directly impact sd LDL levels. Instead, the presence of T2DM or insulin resistance, leading to reduced HDL cholesterol or elevated TG levels, directly contributes to subsequent sd LDL increases, indicating a comprehensive mediating effect. While LDL cholesterol levels correlate positively with sd LDL, they appear unaffected by T2DM or insulin resistance. Importantly, hypertension induced by T2DM or insulin resistance exhibits a positive effect on sd LDL reversal. Unlike T2DM or insulin resistance, blood glucose levels show no significant impact on all processes. It is hoped that these insights might influence the treatment of patients with diabetes and the management of blood parameters in clinical practice. Examining the effect of T2DM or insulin resistance on sd LDL within HDL cholesterol and triglycerides pathways might provide valuable insights for targeted cardiovascular treatments. Additionally, the study's exploration of the potential positive effects of elevated blood pressure on sd LDL reversal may introduce novel considerations for blood pressure management in patients with diabetes.

Association between irisin and vascular complications of type 2 diabetic patients: a prospective case–control study

BackgroundDiabetes vascular complications are classified as either macrovascular (cardiovascular disease) or microvascular (nephropathy). These complications considerably raise the risk of morbidity and death. Irisin is a myokine that has been linked to metabolic disorders and cardiovascular disease. The purpose of this study was to look at the relationship between irisin and vascular complications among type 2 diabetic (T2DM) individuals. In this case–control study, the patients were put into four groups based on the occurrence of a diabetic cardiovascular complications and the presence of diabetic nephropathy into group 1: twenty T2DM cases without complications, group 2: twenty T2DM cases with diabetic nephropathy, group 3: twenty T2DM cases with cardiovascular complications, and group 4: thirty controls. History was taken, and clinical examination was done. Laboratory investigations (fasting blood glucose, 2-h postprandial blood glucose, HbA1C, cholesterol, triglycerides, HDL-C and LDL-C, serum urea and creatinine, albumin/creatinine ratio, eGFR, serum irisin) were analyzed.ResultsSerum level of irisin was significantly lower in T2DM patients than in control. Also, irisin level was significantly lower in diabetic cases with vascular complications versus those without complications. Irisin level had a negative correlation to BMI and lipid profile in diabetic cases and had a positive correlation to eGFR in diabetic patients with cardiovascular complications.ConclusionsIrisin level was significantly lower in T2DM patients than control and in diabetic patients with vascular complications than patients without complications. So, irisin may have a role as a marker of vascular complications in T2DM.

Effect of apigenin on dynamin-related protein 1 in type 1 diabetic rats with cardiovascular complications

Background and ObjectiveCardiovascular complications cause increased mortality rates among diabetics. The molecular mechanisms of aberrant mitochondrial dynamics in diabetes mellitus (DM) are not fully understood. Dynamin-related protein 1 (Drp1) is thought to be a major regulator of mitochondrial fission. There is lack of studies that examined the relationship between apigenin and Drp1 expression in DM. Thus, the current study aimed to explore the expression of Drp1 in diabetic rats with cardiovascular complications, as well as to appraise the role of apigenin in modulating this expression. MethodsTwenty-eight adult male albino Wister rats were randomly and equally allocated into four groups: naive, streptozotocin-induced type 1 diabetic control and two apigenin-injected diabetic groups (early and late). Body weight, heart weight, blood pressure and ECG were recorded. Evaluation of blood glucose level, lipid profile and cardiac functions were measured. Determination of Drp1 mRNA expression, and histological examination of cardiac tissues from the four groups were performed. ResultsDiabetic control rats developed decrease of body weight, increase of blood pressure, deterioration of the normal ECG pattern and upregulation of Drp1 mRNA expression in cardiac tissues. There was a significant correlation between the relative expression of Drp1 and all examined parameters. Apigenin-injection improved fasting blood glucose, lipid profile and cardiac function indicators (i.e., ECG parameters, CK-MB and troponin) as well as the cardiac histological structure. The decrease of Drp1 expression was more evident with early than with late apigenin-injection, however, without statistical significance. ConclusionsIncreased level of Drp1 expression in diabetic rats may be involved in the pathogenesis of diabetic cardiovascular complications. The changes that occurred in response to apigenin injection highlight its potential ameliorative effect on the diabetic cardiovascular complications and pave the route for further investigations.

Diabetic cardiomyopathy in rats was attenuated by endurance exercise through the inhibition of inflammation and apoptosis

Diabetic cardiomyopathy (DCM), as a ventricular dysfunction, is one of the main causes of death in diabetic patients. Former evidence revealed the beneficial effects of exercise on cardiovascular complications of diabetes. We aimed to investigate the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on DCM. Male Wistar rats were divided into control, diabetic, metformin (300 mg/kg), HIIT, MICT, metformin + HIIT, and metformin + MICT diabetic groups. Serum biochemical, inflammatory, and oxidative stress indicators, gene expression of BCL2 and BAX, and histopathologic changes of cardiac tissue were assessed. Our analysis revealed an increase in fasting blood sugar (FBS), creatine kinase MB (CK-MB), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) in diabetes. Also, the superoxide dismutase (SOD) and catalase (CAT) activity, and the total thiol were decreased, in contrast, malondialdehyde (MDA) levels increased in the cardiac tissue of the diabetic group. All of these changes were significantly ameliorated in diabetic animals treated with exercise and metformin + exercise. The level of tumor necrosis factor-α (TNF-α) and Interleukin-1β (IL-1β), as well as the infiltration of inflammatory cells, were decreased in the heart of all exercise training groups. Up-regulation of BCL2 and down-regulation of BAX gene expressions were observed in the cardiac tissue of all exercise-treated groups. In conclusion, HIIT and MICT exercises are effective in preventing DCM development. Exercise training, besides improving oxidative stress and inflammation in cardiac tissue, alleviates cardiac damage by modulating the apoptotic gene expression in diabetic rats.

Essential oil from Fructus Alpiniae zerumbet ameliorates vascular endothelial cell senescence in diabetes by regulating PPAR-γ signalling: A 4D label-free quantitative proteomics and network pharmacology study

Ethnopharmacological relevanceVascular endothelial cell senescence is associated with cardiovascular complications in diabetes. Essential oil from Fructus Alpiniae zerumbet (Pers.) B.L.Burtt & R.M.Sm. (EOFAZ) has potentially beneficial and promising diabetes-related vascular endothelial cell senescence-mitigating effects; however, the underlying molecular mechanisms remain unclear. Aim of the studyTo investigate the molecular effects of EOFAZ on vascular endothelial cell senescence in diabetes. Materials and methodsA diabetes mouse model was developed using a high-fat and high-glucose diet (HFD) combined with intraperitoneal injection of low-dose streptozotocin (STZ, 30 mg/kg) and oral treatment with EOFAZ. 4D label-free quantitative proteomics, network pharmacology, and molecular docking techniques were employed to explore the molecular mechanisms via which EOFAZ alleviates diabetes-related vascular endothelial cell senescence. A human aortic endothelial cells (HAECs) senescence model was developed using high palmitic acid and high glucose (PA/HG) concentrations in vitro. Western blotting, immunofluorescence, SA-β-galactosidase staining, cell cycle, reactive oxygen species (ROS), cell migration, and enzyme linked immunosorbent assays were performed to determine the protective role of EOFAZ against vascular endothelial cell senescence in diabetes. Moreover, the PPAR-γ agonist rosiglitazone, inhibitor GW9662, and siRNA were used to verify the underlying mechanism by which EOFAZ combats vascular endothelial cell senescence in diabetes. ResultsEOFAZ treatment ameliorated abnormal lipid metabolism, vascular histopathological damage, and vascular endothelial aging in diabetic mice. Proteomics and network pharmacology analysis revealed that the differentially expressed proteins (DEPs) and drug-disease targets were associated with the peroxisome proliferator-activated receptor gamma (PPAR-γ) signalling pathway, a key player in vascular endothelial cell senescence. Molecular docking indicated that the small-molecule compounds in EOFAZ had a high affinity for the PPAR-γ protein. Western blotting and immunofluorescence analyses confirmed the significance of DEPs and the involvement of the PPAR-γ signalling pathway. In vitro, EOFAZ and rosiglitazone treatment reversed the effects of PA/HG on the number of senescent endothelial cells, expression of senescence-related proteins, the proportion of cells in the G0/G1 phase, ROS levels, cell migration rate, and expression of pro-inflammatory factors. The protective effects of EOFAZ against vascular endothelial cell senescence in diabetes were aborted following treatment with GW9662 or PPAR-γ siRNA. ConclusionsEOFAZ ameliorates vascular endothelial cell senescence in diabetes by activating PPAR-γ signalling. The results of the present study highlight the potential beneficial and promising therapeutic effects of EOFAZ and provide a basis for its clinical application in diabetes-related vascular endothelial cell senescence.

Cardioprotective and Antifibrotic Effects of Low-Dose Renin-Angiotensin-Aldosterone System Inhibitors in Type 1 Diabetic Rat Model.

Diabetic cardiovascular complications are associated with up to 50% mortality, and current therapies are not effective enough. Renin-angiotensin-aldosterone system inhibitors (RAASis) are the standard of care for diabetic patients with hypertension and albuminuria. Based on our previous studies reporting the renoprotective effects of low-dose RAASis, here, we hypothesized that low-dose RAASi treatment has cardioprotective and antifibrotic benefits in type 1 diabetes mellitus (T1DM). After five weeks of T1DM, adult male Wistar rats received low doses of ramipril, losartan, or eplerenone for two weeks. Heart rate, blood pressure, and pulse wave velocity (PWV) were recorded. Aortic intima-media thickness (IMT), collagen accumulation, and myocardial fibrosis were assessed. All RAASis reduced PWV elevation, prevented the progression of myocardial fibrosis, and normalized B-type natriuretic peptide, troponin I, and fibroblast growth factor 23 levels without affecting blood pressure. Interestingly, only eplerenone reversed the decline in Klotho levels and reduced IMT and fibrosis in the media of the aorta. Our comparative analysis suggests that mineralocorticoid receptor antagonists, particularly eplerenone, may offer superior efficacy in halting both the arterial and the myocardial injuries in T1DM compared to angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers.

Abstract 14798: NAMPT Inhibition Restores Coronary Microvascular Dysfunction in Diabetes

Introduction: Nicotinamide phosphoribosyltransferase (NAMPT) is a multitask peptide; extracellular NAMPT acts as a proinflammatory cytokine, and intracellular NAMPT participates in energy metabolism through NAD + production. Serum NAMPT level is increased in diabetic patients; however, the pathophysiological role of NAMPT in diabetic cardiovascular complications is poorly understood. This study aims to investigate the effect of NAMPT inhibition on coronary microvascular function in diabetes. Materials and Methods: We used two diabetic mouse models: inducible type 2 diabetic (T2D) mice generated by a single injection of low-dose STZ (75 mg/kg, i.p.) with a high-fat diet feeding, and spontaneous T2D mice, TALLYHO/JngJ. Cardiac endothelial cells (CECs) were isolated for molecular biological experiments. Coronary flow velocity reserve (CFVR) was used to determine coronary microvascular function. Results: T2D mice exhibited elevated NAMPT expression in CECs. There was no difference in glucose tolerance and body weight in diabetic NAMPT hetero knockout mice and FK866 (NAMPT inhibitor)-administered diabetic mice compared to their controls. However, CFVR was significantly increased by NAMPT inhibition in T2D mice, accompanied by increased capillary density and augmented endothelium-dependent relaxation (EDR). Chronic administration of neutralizing NAMPT antibody (Ab) also improved CFVR in T2D mice toward the level in control mice. RNA sequencing data in CECs revealed that NAMPT-Ab administration in T2D mice significantly restored the levels of genes related to angiogenesis. NAMPT (100 ng/ml) or NAD + (100 nM) treatment attenuated cell migration in control CECs and reduced EDR in control CAs. Furthermore, NAMPT or NAD + treatment increased mitochondrial ROS formation and decreased Gap junction activity in control CECs. Conclusion: Our data suggest that NAMPT inhibition increases capillary density via enhancing endothelial migration, arguments EDR through reducing mitochondrial ROS production and increasing gap junction activity, and results in restoration of coronary microvascular function in diabetic mice. Therefore, NAMPT inhibition could be a new therapeutic strategy for coronary microvascular disease in diabetes.

Abstract 13004: Blockade of Endothelial to Mesenchymal Transition (EndMT) by an AP-1 Inhibitor Attenuates Atherosclerosis in Diabetes

Background: Atherosclerotic cardiovascular disease is the leading cause of death in individuals with diabetes. Endothelial to mesenchymal transition (EndMT) is characterized by endothelial transformation to a mesenchymal like cellular state. EndMT-mediated endothelial cell dysfunction is known to be involved in cardiovascular complications of diabetes including atherosclerosis. Gene expression changes occur when endothelial cells transition to mesenchymal cells. These transcriptomic changes are regulated by multiple factors including transcription factors (TFs). Although, previous studies have implicated the role of EndMT in atherosclerosis, the role of AP-1 TF complex in EndMT in diabetes induced atherosclerosis is not known. Methods: Single cell transcriptomic (SCT) analysis of diabetic aorta in atheroprone Apoe -/- mice was performed using 10X Genomics platform. In vitro model mimicking diabetes-induced EndMT was established in human aortic endothelial cells (HAECs) using high glucose (25mM) and TNF- α ± a small molecular inhibitor of AP-1, T-5224. RNA and ChIP (chromatin Immunoprecipitation) sequencing was performed. Moreover, Apoe -/- mice made diabetic with streptozotocin, were treated with T-5224 (30 mg/kg daily for 5 weeks) in a 10-week intervention study. Results: SCT analysis of aorta identified increased expression of AP-1 members cFOS and Junb in diabetic endothelial cells in Apoe -/- mice. These genes were also upregulated in the HAECs-based in vitro EndMT model. Interestingly, AP-1 inhibition by T-5224 attenuated EndMT . RNA and ChIP sequencing identified several AP-1 target genes including Col1A2, Col4A1, TGFB, THBD, INSR, PIK3R3 (FDR <0.05, Log2 fold change (2x)) that were common to many enriched pathways including “leukocyte trans-endothelial migration” and “AGE-RAGE signaling pathways in diabetic complications” directly relevant to EndMT in diabetes. Importantly, T-5224 treatment blocked EndMT resulting in reduced atherosclerosis in diabetic Apoe -/- mice. Conclusion: This study identified the AP-1 inhibition with T-5224 as a novel treatment for the first time for the diabetes induced EndMT and atherosclerosis.

Diabetic kidney disease

Diabetes is the leading cause of chronic kidney disease and end stage renal disease (ESRD) globally. Diabetic kidney disease, previously known as diabetic nephropathy, is a general term used for deterioration of kidney function in patients with diabetes. It is important to diagnose and manage diabetic kidney disease early, so as to reduce the incidence of ESRD and the cardiovascular complications of diabetes. This article looks at the epidemiology, presentation and management of diabetic kidney disease.

CADD Studies in the Discovery of Potential ARI (Aldose Reductase Inhibitors) Agents for the Treatment of Diabetic Complications.

The lack of currently available drugs for treating diabetes complications has stimulated our interest in finding new Aldose Reductase inhibitors (ARIs) with more beneficial biological properties. One metabolic method uses aldose reductase inhibitors in the first step of the polyol pathway to control excess glucose flux in diabetic tissues. Computer-aided drug discovery (CADD) is key in finding and optimizing potential lead substances. AR inhibitors (ARI) have been widely discussed in the literature. For example, Epalrestat is currently the only ARI used to treat patients with diabetic neuropathy in Japan, India, and China. Inhibiting R in patients with severe to moderate diabetic autonomic neuropathy benefits heart rate variability. AT-001, an AR inhibitor, is now being tested in COVID-19 to see how safe and effective it reduces inflammation and cardiac damage. In summary, these results from animal and human studies strongly indicate that AR can cause cardiovascular complications in diabetes. The current multi-center, large-scale randomized human study of the newly developed powerful ARI may prove its role in diabetic cardiovascular disease to establish therapeutic potential. During the recent coronavirus disease (COVID-19) outbreak in 2019, diabetes and cardiovascular disease were risk factors for severely negative clinical outcomes in patients with COVID19. New data shows that diabetes and obesity are among the strongest predictors of COVID-19 hospitalization. Patients and risk factors for severe morbidity and mortality of COVID- 19.

RIPK1 and RIPK3 inhibitors: potential weapons against inflammation to treat diabetic complications.

Diabetes mellitus is a metabolic disease that is characterized by chronic hyperglycemia due to a variety of etiological factors. Long-term metabolic stress induces harmful inflammation leading to chronic complications, mainly diabetic ophthalmopathy, diabetic cardiovascular complications and diabetic nephropathy. With diabetes complications being one of the leading causes of disability and death, the use of anti-inflammatories in combination therapy for diabetes is increasing. There has been increasing interest in targeting significant regulators of the inflammatory pathway, notably receptor-interacting serine/threonine-kinase-1 (RIPK1) and receptor-interacting serine/threonine-kinase-3 (RIPK3), as drug targets for managing inflammation in treating diabetes complications. In this review, we aim to provide an up-to-date summary of current research on the mechanism of action and drug development of RIPK1 and RIPK3, which are pivotal in chronic inflammation and immunity, in relation to diabetic complications which may be benefit for explicating the potential of selective RIPK1 and RIPK3 inhibitors as anti-inflammatory therapeutic agents for diabetic complications.

Utilization patterns of cardiovascular medications in patients with diabetes mellitus; a retrospective cross-sectional study, 2013-17.

Diabetes Mellitus (DM) is a prominent health care issue worldwide. One of the most prevalent comorbidities of DM is cardiovascular disease (CVD). The objective of this study was to assess the utilization patterns of cardiovascular medications in patients with DM in Iran from 2013 to 2017. This retrospective cross-sectional study was undertaken using prescription claims data from 2013 to 2017 in Iran. Epidemiological data elements used in this study were obtained from the Global Burden of Disease (GBD) 2019 study. In addition, data on total medication sales were obtained from the national regulatory authority database. The data on medication utilization were analyzed according to the Anatomical Therapeutic Chemical Classification (ATC) /Defined Daily Doses (DDD) international system. Based on the findings, Acetylsalicylic acid was the mainstay of treatment with a utilization rate of 191.7 DDD/ patient/ year in 2017, followed by Atorvastatin with 170.0 and Losartan with 115.1. Although there was an increasing trend in the utilization rate of the medications, the rate of Atenolol and Enalapril was constantly declining during the 2013-17 period. On the other hand, Valsartan and Metoprolol were attracting attention. Almost all medication utilization rates increased from the 30-39 age group up to the 80 + age group. Females had a higher utilization rate in each age group during the whole study period. The present study reflects that medication utilization patterns were rational, according to the standard treatment guidelines. Utilization patterns of medications that are recommended for both prevention and treatment of CVD in diabetes were observed to be the highest. Implementation of further policies is needed to minimize cardiovascular complications of diabetes.