Ichitaro Abe

Glucose Fluctuations Aggravate Cardiac Susceptibility to Ischemia/Reperfusion Injury by Modulating MicroRNAs Expression.

BACKGROUND The influence of glucose fluctuations (GF) on cardiovascular complications of diabetes mellitus (DM) has been attracting much attention. In the present study, whether GF increase susceptibility to ischemia/reperfusion in the heart was investigated. METHODS AND RESULTS Male rats were randomly assigned to either a control, DM, and DM with GF group. DM was induced by an injection of streptozotocin, and glucose fluctuation was induced by starvation and insulin injection. One sequential program comprised 2 hypoglycemic episodes during 4 days. The isolated hearts were subjected to 20-min ischemia/30-min reperfusion. The infarct size was larger in hearts with GF than those with sustained hyperglycemia. Activities of catalase and superoxide dismutase were decreased, and expressions of NADPH oxidase and thioredoxin-interacting protein were upregulated by GF accompanied by an increase of reactive oxygen species (ROS). Swollen mitochondria with destroyed cristae were observed in diabetic hearts; they were further devastated by GF. Microarray analysis revealed that the expressions of microRNA (miRNA)-200c and miRNA-141 were abundant in those hearts with GF. Overexpression of miRNA-200c and miRNA-141 decreased mitochondrial superoxide dismutase and catalase activities, and increased ROS levels. Meanwhile, knockdown of miRNA-200c and miRNA-141 significantly decreased ROS levels in cardiomyocytes exposed to GF. CONCLUSIONS GF increased ROS generation and enhanced ischemia/reperfusion injury in the diabetic heart. Upregulated miRNA-200c and miRNA-141 may account for the increased ROS.

Telmisartan effectively improves insulin sensitivity in hypertensive patients with insulin resistance

SUMMARY OBJECTIVE The angiotensin II receptor blocker (ARB) telmisartan has been shown to activate peroxisome proliferator-activated receptor γ and increase adiponectin protein content in adipocytes. We tested the hypothesis that telmisartan can increase the serum level of adiponectin and improve insulin resistance. METHODS The study participants were 25 consecutive hypertensive patients (8 females, 17 males; 65 ± 10 years). Insulin resistance was defined as a patient showing ≥2.5 in the homeostasis model assessment (HOMA) index. We divided subjects into non-insulin resistance (n = 10) and insulin resistance groups (n = 15) based on the HOMA index. Telmisartan was administered (40 mg/day) was administered for 24 weeks. RESULTS In the insulin resistance group, telmisartan treatment resulted in a significant decrease in the HOMA index and serum level of C-reactive protein, and it increased the serum level of adiponectin (P < 0.05, respectively). Such improvements were not observed in the non-insulin resistance group. Stepwise multiple regression analysis showed that the increase in the serum level of adiponectin was independently associated with reduction in the HOMA index. CONCLUSIONS Our findings suggest that telmisartan improves insulin resistance that parallels an increase in the serum level of adiponectin in hypertensive patients with insulin resistance. It may therefore have advantages in treating such populations.

Association of fibrotic remodeling and cytokines/chemokines content in epicardial adipose tissue with atrial myocardial fibrosis in patients with atrial fibrillation

BACKGROUND Epicardial adipose tissue (EAT) is associated with atrial fibrillation (AF), but the underlying mechanisms remain to be fully elucidated. OBJECTIVE The purpose of this study was to examine, using human left atrial appendage (LAA) samples, the interactive relationship between the EAT profile and atrial myocardial fibrosis through histologic and biochemical analyses. METHODS LAA samples were obtained from 59 consecutive AF patients during cardiovascular surgery. In histologic analysis, adipose tissue, atrial myocardial fibrosis, EAT fibrosis, macrophage infiltration, and matrix metalloproteinase-2 and hypoxia-inducible factor-1α (Hif-1α) expression were evaluated in LAA sections. In biochemical analysis, proinflammatory/fibrotic proteins in EAT, total collagen in left atrial (LA) myocardium, angiopoietin-like protein-2 (Angptl2)-related proteins in EAT, and proinflammatory/fibrotic proteins in serum were evaluated. RESULTS Histology revealed that the severity of fibrotic remodeling of EAT was associated with LA myocardial fibrosis. Immunohistochemical and electron microscopic findings revealed that fibrotic remodeling of EAT was associated with infiltration of macrophages and myofibroblasts. Protein concentration analysis demonstrated that the total collagen in the LA myocardium was positively correlated with proinflammatory and profibrotic cytokines/chemokines, including interleukin-6, monocyte chemoattractant protein-1, tumor necrosis factor-α, vascular endothelial growth factor, and matrix metalloproteinase-2 and matrix metalloproteinase-9 in EAT. The proinflammatory and profibrotic cytokines/chemokines in EAT and the total collagen in the LA were also positively correlated with Angptl2 in EAT. CONCLUSION Our study demonstrated that fibrotic remodeling and cytokines/chemokines in peri-LA EAT were associated with atrial myocardial fibrosis as a substrate of AF. Our results also suggested that overexpression of Hif-1α and Angptl2 may be involved in these processes.

Possible role of rivaroxaban in attenuating pressure-overload-induced atrial fibrosis and fibrillation

BACKGROUND Coagulation factor Xa (FXa) promotes thrombus formation and exacerbates inflammation via activation of protease-activated receptor (PAR)-2. We tested the hypothesis of whether administration of direct oral anticoagulant, rivaroxaban, would attenuate transverse aortic constriction (TAC)-induced atrial inflammatory fibrosis and vulnerability to atrial fibrillation (AF) in mice. METHODS Ten-week-old male CL57/B6 mice were divided into a sham-operation (CNT) group and TAC-surgery group. These two groups were then subdivided into vehicle (VEH) and rivaroxaban (RVX) treatment (30μg/g/day) groups. We assessed PAR-2 expression in response to TAC-related stimulation using rat cultured cells. RESULTS TAC-induced left atrial thrombus formation was not observed in the TAC-RVX group. Cardiac PAR-2 upregulation was observed in both TAC groups. In the quantitative analysis of mRNA levels, cardiac PAR-2 upregulation was attenuated in the TAC-RVX group compared to TAC-VEH group. In histological evaluation, the TAC-VEH group showed cardiac inhomogeneous interstitial fibrosis and abundant infiltration of macrophages, which were attenuated by RVX administration. Electrophysiological examination revealed that AF duration in the TAC group was shortened by RVX administration. TAC-induced protein overexpression of monocyte chemoattractant protein-1, and mRNA overexpression of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 in the left atrium was suppressed by RVX treatment. In cardiac fibroblasts, persistent intermittent stretch upregulated PAR-2, which was suppressed by RVX pre-incubation. CONCLUSIONS These observations demonstrate that coagulation FXa inhibitor probably has a cardioprotective effect against pressure-overload-induced atrial remodeling.

Role of atrial endothelial cells in the development of atrial fibrosis and fibrillation in response to pressure overload

BACKGROUND Monocyte chemoattractant protein-1 (MCP-1)-mediated inflammatory mechanisms have been shown to play a crucial role in atrial fibrosis induced by pressure overload. In the present study, we investigated whether left atrial endothelial cells would quickly respond structurally and functionally to pressure overload to trigger atrial fibrosis and fibrillation. METHODS AND RESULTS Six-week-old male Sprague-Dawley rats underwent suprarenal abdominal aortic constriction (AAC) or a sham operation. By day 3 after surgery, macrophages were observed to infiltrate into the endocardium. The expression of MCP-1 and E-selectin in atrial endothelium and the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and ED1 in left atrial tissue were enhanced. Atrial endothelial cells were irregularly hypertrophied with the disarrangement of lines of cells by scanning electron microscopy. Various-sized gap formations appeared along the border in atrial endothelial cells, and several macrophages were located just in the endothelial gap. Along with the development of heterogeneous interstitial fibrosis, interatrial conduction time was prolonged and the inducibility of atrial fibrillation by programmed extrastimuli was increased in the AAC rats compared to the sham-operated rats. CONCLUSIONS Atrial endothelium responds rapidly to pressure overload by expressing adhesion molecules and MCP-1, which induce macrophage infiltration into the atrial tissues. These processes could be an initial step in the development of atrial remodeling for atrial fibrillation.

Interleukin 10 Treatment Ameliorates High-Fat Diet–Induced Inflammatory Atrial Remodeling and Fibrillation

Background: Obesity, characterized by systemic low-grade inflammation, is considered a well-known risk for atrial fibrillation. In fact, IL-10 (interleukin 10), which is a potent anti-inflammatory cytokine, has been reported to decrease in obese and diabetic patients. We tested the hypotheses forwarding that genetic deletion of IL-10 exacerbates high-fat diet (HFD)–induced obesity-caused atrial inflammation, lipidosis, fibrosis, and fibrillation and that IL-10 therapy inhibits this pathology. Methods: Eight- to 10-week-old male CL57/B6 (wild-type) mice and IL-10 knockout mice were divided into a 12-week HFD group and a 12-week normal-fat diet (NFD) group, respectively. In addition, the effect of IL-10 administration was also investigated. Results: HFD-induced obesity for 12 weeks significantly depressed serum levels of IL-10 but were found to increase several proinflammatory cytokines in wild-type mice. Adverse atrial remodeling, including atrial inflammation, lipidosis, and fibrosis, was induced in both wild-type and IL-10 knockout mice by HFD. Vulnerability to atrial fibrillation was also significantly enhanced by HFD. With regard to epicardial and pericardial adipose tissue, the total amount of epicardial adipose tissue+pericardial adipose tissue volume was increased by HFD. Besides, proinflammatory and profibrotic cytokines of epicardial adipose tissue+pericardial adipose tissue were also upregulated. In contrast, the protein level of adiponectin was downregulated by HFD. These HFD-induced obesity-caused adverse effects were further exaggerated in IL-10 knockout mice in comparison to wild-type mice. Systemic IL-10 administration markedly ameliorated HFD-induced obesity-caused left atrial remodeling and vulnerability to atrial fibrillation, in addition to improving the quality of epicardial adipose tissue+pericardial adipose tissue. Conclusions: Our results highlight IL-10 treatment as a potential therapeutic approach to limit the progression of HFD-induced obesity-caused atrial fibrillation.

Interleukin-10 treatment attenuates sinus node dysfunction caused by streptozotocin-induced hyperglycaemia in mice

Aims Diabetes, characterized by hyperglycaemia, causes sinus node dysfunction (SND) in several rodent models. Interleukin (IL)-10, which is a potent anti-inflammatory cytokine, has been reported to decrease in obese and diabetic patients. We tested the hypothesis that administration of IL-10 inhibits the development of SND caused by hyperglycaemia in streptozotocin (STZ)-induced diabetic mice. Methods and results Six-week old CL57/B6 (WT) mice were divided into the following groups: control, STZ injection, and STZ injection with systemic administration of IL-10. IL-10 knockout mice were similarly treated. STZ-induced hyperglycaemia for 8 weeks significantly depressed serum levels of IL-10, but increased several proinflammatory cytokines in WT mice. STZ-induced hyperglycaemia-reduced resting heart rate (HR), and attenuated HR response to isoproterenol in WT mice. In isolated perfused heart experiments, corrected-sinus node recovery time was prolonged in WT mice with STZ injection. Sinus node tissue isolated from the WT-STZ group showed fibrosis, abundant infiltration of macrophages, increased production of reactive oxygen species (ROS), and depressed hyperpolarization activated cyclic nucleotide-gated potassium channel 4 (HCN4). However, the changes observed in the WT-STZ group were significantly attenuated by IL-10 administration and were further exaggerated in IL-10 knockout mice. In cultured cells, preincubation of IL-10 suppressed hyperglycaemia-induced apoptotic and profibrotic signals, and overproduction of ROS. IL-10 markedly inhibited the high glucose-induced p38 activation, and activated signal transducer and activator of transcription (STAT) 3 phosphorylation. Conclusions Our results suggest that IL-10 attenuates ROS production, inflammation and fibrosis, and plays an important role in the inhibition of hyperglycaemia-induced SND by suppression of HCN4 downregulation. In addition, IL-10-mediated inhibition of p38 is dependent on STAT3 phosphorylation.