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BackgroundMyocardial fibrosis is an essential hallmark of diabetic cardiomyopathy (DCM) contributing to cardiac dysfunctions. Resveratrol, an antioxidant, exerts its anti-fibrotic effect via inhibition of oxidative stress, while the underlying molecular mechanism remains largely elusive. Periostin, a fibrogenesis matricellular protein, has been shown to be associated with oxidative stress. In the present study, we investigated the role of periostin in anti-fibrotic effect of resveratrol in streptozocin (STZ)-induced diabetic heart and the underlying mechanisms.MethodsDiabetic mice were induced by STZ injection. After treatment with resveratrol (5 or 25 mg/kg/day i.g) or Saline containing 0.5 % carboxymethyl cellulose (CMC) for 2 months, the hearts were detected for oxidative stress and cardiac fibrosis using western blot, Masson’s trichrome staining and Dihydroethidium (DHE) staining. In in vitro experiments, proliferation and differentiation of fibroblasts under different conditions were investigated through western blot, 3-(4,5)-dimethylthiahiazo (−z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay and immunofluorescence staining.ResultsAdministration of resveratrol significantly mitigated oxidative level, interstitial fibrosis and expressions of related proteins in STZ-induced diabetic hearts. In in vitro experiments, resveratrol exhibited anti-proliferative effect on primary mouse cardiac fibroblasts via inhibiting reactive oxygen species (ROS)/extracellular regulated kinase (ERK) pathway and ameliorated myofibroblast differentiation via suppressing ROS/ERK/ transforming growth factor β (TGF-β)/periostin pathway.ConclusionIncreased ROS production, activation of ERK/TGF-β/periostin pathway and myocardial fibrosis are important events in DCM. Alleviated ROS genesis by resveratrol prevents myocardial fibrosis by regulating periostin related signaling pathway. Thus, inhibition of ROS/periostin may represent a novel approach for resveratrol to reverse fibrosis in DCM.

Oxidative stress is considered to be a critical factor in diabetes-induced endothelial progenitor cell (EPC) dysfunction, although the underlying mechanisms are not fully understood. In this study, we investigated the role of high mobility group box-1 (HMGB-1) in diabetes-induced oxidative stress. HMGB-1 was upregulated in both serum and bone marrow-derived monocytes from diabetic mice compared with control mice. In vitro, advanced glycation end productions (AGEs) induced, expression of HMGB-1 in EPCs and in cell culture supernatants in a dose-dependent manner. However, inhibition of oxidative stress with N-acetylcysteine (NAC) partially inhibited the induction of HMGB-1 induced by AGEs. Furthermore, p66shc expression in EPCs induced by AGEs was abrogated by incubation with glycyrrhizin (Gly), while increased superoxide dismutase (SOD) activity in cell culture supernatants was observed in the Gly treated group. Thus, HMGB-1 may play an important role in diabetes-induced oxidative stress in EPCs via a positive feedback loop involving the AGE/reactive oxygen species/HMGB-1 pathway.

iabetes mellitus (DM) is one of the most important risk factors of cardiovascular diseases, and numerous patients who are afflicted with diabetes usually suffer the diffused stenosis of coronary arteries, leading to dreadful consequences such as myocardial infarction and cardiomyopathy. Non-invasive evaluation tools such as Doppler echocardiography demonstrate the impairment of cardiac function in diabetic animal models as well as in diabetic patients, 1,2 whereas the mechanism is still not well elucidated.Neuropathy is one of the common complications of diabetes, which could result in the degeneration of the nerve fibers both in diabetic animals and patients. 3-5 Transient Receptor Potential Vanilloid 1 (TRPV1) is a non-selective cation channel and is diversely distributed in terminals of sensory nerve fibers, dorsal root ganglia (DRG), spinal cord, and many other various regions in the brain. 6 It could lead to the release of neurotransmitters such as calcitonin generelated peptide (CGRP) from peripheral nerve terminals when activated by capsaicin, protons, noxious heat, etc. 7,8 It has been found that in diabetes-prone NOD mice, the protein expression and function of TRPV1 was significantly depressed in DRG. 9 Using immunohistochemical staining, TRPV1 was also found to be reduced in epineurial arterioles in long-term diabetic rats. 10 These investigations suggest that the expression of TRPV1 is susceptible to diabetes. In addition, recent studies disclose that TRPV1 is expressed in the myocardium and perivascular region, which are close to the epicardial surface of ventricles. 11 We revealed that the expression of TRPV1 in diabetic hearts was significantly suppressed in our previous study. 12 However, the impact of the decreased TRPV1 on the diabetic heart has not been investigated yet.A few studies have revealed that TRPV1 can serve as a molecular integrator of various noxious stimuli, especially the myocardial ischemia, in order to protect the hearts against ischemic injury. 11,13 For example, exogenous agonists of TRPV1 exert a cardioprotective effect on ischemia/reperfusion injury, whereas TRPV1 gene knockout eliminates the protection. 14,15 Therefore, it is reasonable to hypothesize that the alteration of TRPV1 secondary to diabetes can be related to the severe postischemic injury of the heart.In the present study, we measure the expression of TRPV1 and CGRP in diabetic hearts and investigate the effect of TRPV1 on the cardiac function after ischemia injury. The results might help explain the vulnerability of diabetic hearts to ischemic injury.

High mobility group box-1 (HMGB-1), a typical damage-associated molecular pattern protein released from various cells, was first identified in 1973. It is usually stored in the nuclei of cells. Several modifications of HMGB-1 promote its translocation to the cytosol, and it is actively or passively released from cells. When outside of the cells, HMGB-1is crucial in inflammation. It exerts its biological functions via interaction with its receptors, including receptor for advanced glycation end products (RAGE) and Toll-like receptor 4(TLR4). A large number of studies showed a close link between inflammation and thrombosis. This review demonstrated the increased expression of HMGB-1 in thrombosis-related diseases, including coronary artery disease, stroke, peripheral arterial disease, disseminated intravascular coagulation, and venous thrombosis. Besides, it summarized the current understanding of the emerging link between HMGB-1 and thrombosis from three aspects: platelet, NETs, and coagulation and fibrinolysis factors. Finally, it explored the possible therapeutic strategies targeting HMGB-1 for treating thrombosis-related diseases.

Background: The ischemia/reperfusion (I/R) process in patients with ST-segment elevation myocardial infarction (STEMI) triggers an immune response, resulting in myocyte death. Krüppel-Like Factor 2 (KLF2), which is highly expressed in endothelial cells (ECs) under laminar flow, exerts anti-inflammatory effects. In this study, we explored the role of small extracellular vesicles (EVs) from KLF2-overexpressing ECs (KLF2-EVs) in the immunomodulation and its implications in myocardial I/R injury. Methods and Results: The small EVs were isolated from KLF2-overexpressing ECs' supernatant using gradient centrifugation. Mice were subjected to 45 min of ischemia followed by reperfusion, and KLF2-EVs were administrated through intravenous injection. KLF2-EVs ameliorated I/R injury and alleviated inflammation level in the serum and heart. We employed the macrophage depletion model and splenectomy and showed that Ly6C high monocyte recruitment from bone marrow was the main target of KLF2-EVs. miRNA-sequencing of KLF2-EVs and bioinformatics analysis implicated miRNA-24-3p (miR-24-3p) as a potent candidate mediator of monocyte recruitment and CCR2 as a downstream target. miR-24-3p mimic inhibited the migration of Ly6C high monocytes, and miR-24-3p antagomir reversed the effect of KLF2-EVs in myocardial I/R. Conclusion: Our data demonstrated that KLF2-EVs attenuated myocardial I/R injury in mice via shuttling miR-24-3p that restrained the Ly6C high monocyte recruitment. Thus, KLF2-EVs could be a potential therapeutic agent for myocardial I/R injury.

Background The triglyceride glucose (TyG) index has been proposed as a reliable marker of insulin resistance (IR) and an independent predictor of cardiovascular disease risk. However, its prognostic value in patients with acute decompensated heart failure (ADHF) remains unclear. Methods A total of 932 hospitalized patients with ADHF from January 1st, 2018 to February 1st, 2021 were included in this retrospective study. The TyG index was calculated as ln [fasting triglyceride level (mg/dL) × fasting plasma glucose level (mg/dL)/2]. Patients were divided into tertiles according to TyG index values. The primary endpoints were all-cause death, cardiovascular (CV) death and major adverse cardiac and cerebral events (MACCEs) during follow-up. We used multivariate adjusted Cox proportional hazard models and restricted cubic spline analysis to investigate the associations of the TyG index with primary endpoints. Results During a median follow-up time of 478 days, all-cause death, CV death and MACCEs occurred in 140 (15.0%), 103 (11.1%) and 443 (47.9%) cases, respectively. In multivariate Cox proportional hazard models, the risk of incident primary endpoints was associated with the highest TyG tertile. After adjustment for confounding factors, hazard ratios (HRs) for the highest tertile (TyG index ≥ 9.32) versus the lowest tertile (TyG index < 8.83) were 2.09 (95% confidence interval [CI], 1.23–3.55; p = 0.006) for all-cause death, 2.31 (95% CI, 1.26–4.24; p = 0.007) for CV death and 1.83 (95% CI, 1.18–3.01; p = 0.006) for MACCEs. Restricted cubic spline analysis also showed that the cumulative risk of primary endpoints increased as TyG index increased. When the TyG index was used as a continuous variable, the hazard ratios of the three primary endpoints rapidly increased within the higher range of the TyG index (all cause death, TyG > 9.08; CV death, TyG > 9.46; MACCEs, TyG > 9.87). Conclusions The elevated TyG index was independently associated with poor prognosis, and thus would be useful in the risk stratification in patients with ADHF.

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