Diabetic Ischemic Heart Disease Research Articles

Transcriptome wide changes in long noncoding RNAs in diabetic ischemic heart disease

More than 10% of adults in the United States have type 2 diabetes mellitus (DM) with a 2–4 times higher prevalence of ischemic heart disease than the non-diabetics. Despite extensive research approaches to limit this life-threatening condition have proven unsuccessful, highlighting the need for understanding underlying molecular mechanisms. Long noncoding RNAs (lncRNAs), which regulate gene expression by acting as signals, decoys, guides, or scaffolds have been implicated in diverse cardiovascular conditions. However, their role in ischemic heart disease in DM remains poorly understood. We provide new insights into the lncRNA expression profile after ischemic heart disease in DM mice. We performed unbiased RNA sequencing of well-characterized type 2 DM model db/db mice or its control db/+ subjected to sham or MI surgery. Computational analysis of the RNA sequencing of these LV tissues identified several differentially expressed lncRNAs between (db/db sham vs. db/db MI) including Gm19522 and Gm8075. lncRNA Gm-19522 may regulate DNA replication via DNA protein kinases, while lncRNA Gm-8075 is associated with cancer gene dysregulation and PI3K/Akt pathways. Thus, the downregulation of lncRNAs Gm19522 and Gm8075 post-MI may serve as potential biomarkers or novel therapeutic targets to improve cardiac repair/recovery in diabetic ischemic heart disease.

Polymorphisms and Gene-Gene Interaction in AGER/IL6 Pathway Might Be Associated with Diabetic Ischemic Heart Disease.

Background: Although the genetic susceptibility to diabetes and ischemic heart disease (IHD) has been well demonstrated, studies aimed at exploring gene variations associated with diabetic IHD are still limited; Methods: Our study included 204 IHD cases who had been diagnosed with diabetes before the diagnosis of IHD and 882 healthy controls. Logistic regression was used to find the association of candidate SNPs and polygenic risk score (PRS) with diabetic IHD. The diagnostic accuracy was represented with AUC. Generalized multifactor dimensionality reduction (GMDR) was used to illustrate gene-gene interactions; Results: For IL6R rs4845625, the CT and TT genotypes were associated with a lower risk of diabetic IHD than the CC genotype (OR = 0.619, p = 0.033; OR = 0.542, p = 0.025, respectively). Haplotypes in the AGER gene (rs184003-rs1035798-rs2070600-rs1800624) and IL6R gene (rs7529229-rs4845625-rs4129267-rs7514452-rs4072391) were both significantly associated with diabetic IHD. PRS was associated with the disease (OR = 1.100, p = 0.005) after adjusting for covariates, and the AUC were 0.763 (p < 0.001). The GMDR analysis suggested that rs184003 and rs4845625 were the best interaction model after permutation testing (p = 0.001) with a cross-validation consistency of 10/10; Conclusions: SNPs and haplotypes in the AGER and IL6R genes and the interaction of rs184003 and rs4845625 were significantly associated with diabetic IHD.

Effects of protein disulfide isomerase on hyperglycemia and hypoxia/reoxygenation injury in H9c2 cardiomyocytes

Objective: To explore the effect of protein disulfide isomerase (PDI) in diabetic ischemic heart disease. Methods: We established an in vitro model of high glucose and hypoxia/reoxygenation in H9c2 rat myocardial cells. Cultured cells were divided into four groups: Control, high glucose (HG), hypoxia/reoxygenation (H/R) and HG+H/R. Changes in PDI expression mediated by PDI adenovirus(Ad-PDI) infection and siRNA(PDI-siRNA) transfection in myocardial cells were observed by inverted fluorescence microscopy. We also measured lactate dehydrogenase(LDH) activity and malondialdehyde(MDA) and high molecular weight(HMW)-APN concentrations. PDI, APN, cleaved caspase-3, and glucose regulated protein 78 (Grp78) protein expression were detected. Results: PDI expression was significantly decreased in the HG, H/R and HG+H/R groups compared to the Control group; however, LDH activity[(179.7±10.4) U/L、(218.4±18.4) U/L、(328.2±5.3) U/L vs (91.0±11.0) U/L], MDA concentration[(7.0±0.4) μmol/L、(10.0±1.0) μmol/L、(11.7±1.0) μmol/L vs (4.2±1.8) μmol/L], cleaved caspase-3, and Grp78 expression were increased. Interestingly, APN and HMW-APN expression were decreased [(2.01±0.21) μg/L、(1.64±0.27) μg/L、(1.20±0.14) μg/L vs (2.62±0.12) μg/L, all P<0.05]. Over expression of PDI attenuated high glucose and hypoxia/reoxygenation induced apoptosis and oxidative stress in H9c2 cardiomyocytes(all P<0.05), and simultaneously increased APN and HMW-APN expression [(2.86±0.03) μg/L vs (3.03±0.10) μg/L、(2.06±0.05) μg/L vs (2.31±0.06) μg/L、(1.83±0.07) μg/L vs (1.96±0.11) μg/L、(1.20±0.06) μg/L vs (1.39±0.09) μg/L]. PDI-siRNA transfection increased LDH activity, MDA concentration, and cleaved caspase-3 and Grp78 expression, and decreased APN and HMW-APN expression [(0.75±0.09) μg/L vs (0.59±0.09) μg/L、(0.62±0.04) μg/L vs (0.53±0.05) μg/L、(0.55±0.14) μg/L vs (0.51±0.12) μg/L、(0.48±0.12) μg/L vs (0.35±0.08) μg/L] in response to different treatments in cultured H9c2 cardiomyocytes (all P<0.05). Conclusion: PDI may regulate the expression of APN and HMW-APN, and play an important role in the function of diabetic ischemia-reperfusion cardiomyocytes.

Naringenin alleviates myocardial ischemia reperfusion injury by enhancing the myocardial miR-126-PI3K/AKT axis in streptozotocin-induced diabetic rats.

Ischemic heart disease (IHD) is a leading cause of death in patients with type 1 diabetes. The key to treating IHD is to restore blood supply to the ischemic myocardium, which inevitably causes myocardial ischemia reperfusion (MI/R) injury. Although naringenin (Nar) prevents MI/R injury, the role of Nar in diabetic MI/R (D-MI/R) injury remains to be elucidated. The PI3K/AKT signaling pathway and microRNA (miR)-126 have previously been shown to serve anti-MI/R injury roles. The present study aimed to investigate the protection of Nar against D-MI/R injury and the role of the miR-126-PI3K/AKT axis. Diabetic rats were treated distilled water or Nar (25 or 50 mg/kg, orally) for 30 days and then exposed to MI/R. The present results revealed that Nar alleviated MI/R injury in streptozotocin (STZ)-induced diabetic rats, as shown below: the reduction myocardial enzymes levels was measured using spectrophotometry, the increase of cardiac viability was detected by MTT assay, the inhibition of myocardial oxidative stress was measured using spectrophotometry and the enhancement of cardiac function were recorded using a hemodynamic monitoring system. Furthermore, Nar upregulated the myocardial miR-126-PI3K/AKT axis in D-MI/R rats. These results indicated that Nar alleviated MI/R injury through upregulating the myocardial miR-126-PI3K/AKT axis in STZ-induced diabetic rats. The current findings revealed that Nar, as an effective agent against D-MI/R injury, may provide an effective approach in the management of diabetic IHD.

Incidence of heart failure among diabetic patients with ischemic heart disease: a cohort study

BackgroundIn population studies of heart failure (HF), diabetes has been shown to be an independent risk factor. However, the evidence evaluating diabetes mellitus (DM) as an independent risk factor in incident HF in patients with ischemic heart disease (IHD) is scarce. Our study aimed to assess the incidence of HF in diabetic IHD patients compared to non-diabetic IHD patients in Ethiopia.MethodsA retrospective cohort study was conducted among 306 patients with IHD followed-up at Tikur Anbessa Specialized Hospital in Addis Ababa, Ethiopia. The IHD patients who did not have HF at baseline were followed for 24 months beginning from November 30, 2015. We assessed the incidence of HF in patients with diabetic IHD versus the non-diabetic IHD. Cox proportional hazards models were used to assess the association between diabetic IHD and HF after controlling for important covariates. Hypertension was examined as a possible effect modifier as well.ResultsThe mean age was 56.8 years, 69% were male, and 31% were diabetic. During the 24 months follow-up period, 196 (64.1%) had incident HF. On multivariate Cox regression, DM was significantly associated with incident HF [Hazard Ratio = 2.04, 95% confidence interval (CI): 1.32–3.14, p = 0.001]. Furthermore, when the patients were stratified by hypertension (HTN), DM was associated with worse prognosis, the strongest association being in those with co-existing DM and HTN [HR = 2.57,95% CI =1.66–3.98, p < 0.0001] followed by the presence of DM without HTN [HR 2.27, 95% CI = 1.38–3.71, p = 0.001] (compared to those with neither).ConclusionDM is the strongest predictor of incident HF, compared to other traditional risk factors, in Ethiopian patients with IHD. Those with both DM and HTN are at the highest risk.

Role of N-(carboxymethyl)lysine in the development of ischemic heart disease in type 2 diabetes mellitus.

This study aims to determine the levels of Nε-(carboxymethyl)lysine (CML) in patients with Type 2 diabetic patients with and without ischemic heart disease (IHD) and to find for a possible association between circulating CML and a number of clinical parameters including lipids, hemoglobin A1c (HbA1c) and malondialdehyde (MDA) in Type 2 diabetic IHD patients. Serum CML levels were measured by enzyme-linked immunosorbent assay using polyclonal anti-CML antibodies. Serum levels of CML and MDA were assessed in 60 IHD patients with Type 2 diabetes, 43 IHD patients without Type 2 diabetes, 64 Type 2 diabetics without IHD, and 80 sex- and age-matched healthy subjects. Correlations studies between CML levels and lipids, HbA1c, and lipid peroxidation were performed in Type 2 diabetes patients with and without IHD. A statistical significance was observed in the levels of serum glucose, lipids (triglyceride, total cholesterol, HDL-cholesterol), MDA, HbA1c, CML and LDL-cholesterol (p<0.05) between the groups of the study. CML levels were significantly increased in diabetic IHD patients compared with Type 2 diabetes patients but without IHD (537.1 ± 86.1 vs 449.7 ± 54.9, p<0.001). A positive correlation was observed between serum levels of CML and MDA, r = 0.338 (p = 0.008) in Type 2 diabetes patients with IHD. However, age, HbA1c and lipids had no significant influence on CML levels among diabetics (p>0.05). In conclusion, this study demonstrates the effect of both diabetes and oxidative stress on the higher levels of circulating CML. These results showed that increased serum levels of CML are associated with the development of IHD in Type 2 diabetes mellitus.