Pathogenetic mechanisms of septic cardiomyopathy.

Sepsis is a serious complication after infection, whose further development may lead to multiple organ dysfunction syndrome and so on. It is an important cause of death in critically ill patients who suffered an infection. Sepsis cardiomyopathy is a common complication that exacerbates the prognosis of patients. At present, though the pathogenesis of sepsis cardiomyopathy is not completely clear, in-depth study of the pathogenesis of sepsis cardiomyopathy and the discovery of its potential therapeutic targets may decrease the mortality of sepsis patients and bring clinical benefits. This article reviews mitochondrial dysfunction, mitophagy, oxidation stress, and other mechanisms in sepsis cardiomyopathy.

Inhibiting miR-205 Alleviates Cardiac Ischemia/Reperfusion Injury by Regulating Oxidative Stress, Mitochondrial Function, and Apoptosis.

BACKGROUND: miR-205 is important for oxidative stress, mitochondrial dysfunction, and apoptosis. The roles of miR-205 in cardiac ischemia/reperfusion (I/R) injury remain unknown. The aim of this research is to reveal whether miR-205 could regulate cardiac I/R injury by focusing upon the oxidative stress, mitochondrial function, and apoptosis. METHODS: Levels of miR-205 and Rnd3 were examined in the hearts with I/R injury. Myocardial infarct size, cardiac function, oxidative stress, mitochondria function, and cardiomyocyte apoptosis were detected in mice with myocardial ischemia/reperfusion (MI/R) injury. The primary neonatal cardiomyocytes underwent hypoxia/reoxygenation (H/R) to simulate MI/R injury. RESULTS: miR-205 levels were significantly elevated in cardiac tissues from I/R in comparison with those from Sham. In comparison with controls, levels of Rnd3 were significantly decreased in the hearts from mice with MI/R injury. Furthermore, inhibiting miR-205 alleviated MI/R-induced apoptosis, reduced infarct size, prevented oxidative stress increase and mitochondrial fragmentation, and improved mitochondrial functional capacity and cardiac function. Consistently, overexpression of miR-205 increased infarct size and promoted apoptosis, oxidative stress, and mitochondrial dysfunction in mice with MI/R injury. In cultured mouse neonatal cardiomyocytes, downregulation of miR-205 reduced oxidative stress in H/R-treated cardiomyocytes. Finally, inhibiting Rnd3 ablated the cardioprotective effects of miR-205 inhibitor in MI/R injury. CONCLUSIONS: We conclude that inhibiting miR-205 reduces infarct size, improves cardiac function, and suppresses oxidative stress, mitochondrial dysfunction, and apoptosis by promoting Rnd3 in MI/R injury. miR-205 inhibitor-induced Rnd3 activation is a valid target to treat MI/R injury.

Engineered macrophage membrane-enveloped nanomedicine for ameliorating myocardial infarction in a mouse model.

Myocardial infarction (MI) is the serious condition causing lots of death over the world. Myocytes apoptosis, inflammation, and fibrosis are three important factors implicated in pathogenesis of MI. Targeting these three factors has been shown to ameliorate MI and rescue cardiac function. Previous studies have demonstrated that microRNA (miR) 199a-3p protect against MI. In this study, we prepare macrophage membrane coated nanoparticles (MMNPs) containing miR199a-3p. We evaluate the effects of these NPs on apoptosis and cell proliferation in vitro and the effects on inflammation cytokine production, expression of fibrosis related proteins, cardiac injuries, and functions in MI mice. We find that the MMNPs have receptors of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) and can bind to these cytokines. MMNPs prevent hypoxia-induced apoptosis and promote cell proliferation, suppress the inflammation, and inhibit the cardiac fibrosis in MI mice. These results demonstrate that MMNPs ameliorate left ventricular remodeling and cardiac functions, and protect against MI, suggesting MMNPs containing miR199a-3p is a potential therapeutic approach to treat MI.

Mechanical stretch promotes antioxidant responses and cardiomyogenic differentiation in P19 cells.

Accumulating evidence has suggested that mechanical stimuli play a crucial role in regulating the lineage-specific differentiation of stem cells through fine-tuning redox balance. We aimed to investigate the effects of cyclic tensile strain (CTS) on the expression of antioxidant enzymes and cardiac-specific genes in P19 cells, a widely characterized tool for cardiac differentiation research. A stretching device was applied to generate different magnitude and duration of cyclic strains on P19 cells. The messenger RNA and protein levels of targeted genes were determined by real-time polymerase chain reaction and Western blot assays, respectively. Proper magnitude and duration of cognitive stimulation therapy (CST) stimulation substantially enhanced the expression of both antioxidant enzymes and cardiac-specific genes in P19 cells. Sirtuin 1 (SIRT1) played an essential role in the CTS-induced cardiomyogenic differentiation of P19, as evidenced by changes in the expression of antioxidant enzymes and cardiac-specific genes. Mechanical loading promoted the cardiomyogenic differentiation of P19 cells. SIRT1 was involved in CST-mediated P19 differentiation, implying that SIRT1 might serve as an important target for developing methods to promote cardiomyogenic differentiation of stem cells.

Irisin attenuates angiotensin II-induced cardiac fibrosis via Nrf2 mediated inhibition of ROS/ TGFß1/Smad2/3 signaling axis.

Angiotensin II-related cardiac fibrosis is one of the key pathological changes of the hypertrophied left ventricle in various heart disease. Irisin was recently reported to confer cardio-protective and anti-oxidative effects, while whether it can reverse the renin-angiotensin-aldosterone system(RAAS) activation related(angiotensin II-induced) cardiac fibrosis is unknown. In this study, we found that angiotensin II-induced cardiac dysfunction and fibrotic responses were dampened by irisin treatment in mice. Mechanistically, angiotensin II induced robust ROS generation, which in turn triggered activation of pro-fibrotic TGFß1-Smad2/3 signaling and subsequent collagen synthesis and fibroblast-myofibroblast transformation in cardiac fibroblasts. In contrast, Irisin treatment suppressed angiotensin II-induced ROS generation, TGFß1 activation, collagen synthesis and fibroblast-myofibroblast transformation, the effects of which was accompanied by Nrf2 activation and also abolished by a Nrf2 targeted siRNA. Taken together, we here identified irisin as a promising anti-fibrotic therapeutic for angiotensin II-related cardiac fibrosis.

The Protective Effects of Preconditioning With Dioscin on Myocardial Ischemia/Reperfusion-Induced Ventricular Arrhythmias by Increasing Connexin 43 Expression in Rats.

Myocardial ischemia-reperfusion (IR) injury is associated with high disability and mortality worldwide. This study was to explore the roles of dioscin in the myocardial IR rats and discover the related molecular mechanisms. Rats were divided into 5 groups: sham, IR, IR + 15 mg/kg dioscin, IR + 30 mg/kg dioscin, and IR + 60 mg/kg dioscin. Heart rate (HR), mean arterial blood pressure (MAP), and rate pressure product (RPP) were evaluated at 10 minutes before ischemia, immediately after ischemia, and at the beginning, middle, and end of reperfusion. Arrhythmia score and myocardial infarct size were examined in rats of all groups. The serum creatine kinase-muscle/brain (CKMB) and cardiac troponin I (cTnI) levels were analyzed via enzyme-linked immunosorbent assay. Protein amount of total connexin 43 (T-Cx43) and phosphorylated connexin 43 (P-Cx43) was evaluated by Western blot. Ischemia reperfusion significantly decreased HR, MAP, and RPP of rats compared to the sham group. However, dioscin significantly attenuated the above phenomena in a dose-dependent manner. Dioscin markedly inhibited IR-induced increase in arrhythmias score, infarct size, and serum CKMB and cTnI levels. In addition, dioscin strikingly induced IR-repressed expression of T-Cx43 and P-Cx43. Our results suggested that dioscin pretreatment exhibited protective effects against myocardial IR injury. Moreover, we found that dioscin attenuated myocardial IR-induced ventricular arrhythmias via upregulating Cx43 expression and activation.

Astaxanthin ameliorates cardiomyocyte apoptosis after coronary microembolization by inhibiting oxidative stress via Nrf2/HO-1 pathway in rats.

Coronary microembolization (CME) caused by physical obstruction in coronary microcirculation induces myocardial apoptosis and cardiac dysfunction, and it was reported that the inactivation of the Nrf2/HO-1 signaling was involved in this process. Astaxanthin (AST) is a reddish pigment that belongs to keto-carotenoids. It is also a potent antioxidant and has been reported to activate Nrf2/HO-1 signaling in vein endothelial cells. However, it is still unknown whether AST is able to activate Nrf2/HO-1 signaling pathway to protect cardiac functions from CME in vivo. To address this question, rats were orally administrated with AST or AST plus Zinc protoporphyrin IX (ZnPP, a HO-1 inhibitor), followed by CME modeling operation. Then, cardiac function was evaluated by echocardiographic measurement. Myocardial infarction was measured by HBFP staining, and apoptosis was assessed by TUNEL staining. The protein levels and mRNA expressions of Bax and Bcl-2 were measured by Western blot and qRT-PCR, respectively. ELISA was performed to measure the activity of enzymes related to oxidative stress. AST pretreatment dramatically attenuated CME-induced cardiac dysfunction, myocardial infarction, and cardiomyocyte apoptosis. Mechanistically, AST suppressed CME-induced oxidative stress by re-activating Nrf2/HO-1 signaling. HO-1 inhibitor ZnPP completely eliminated the benefits of AST in CEM, supporting the critical role of Nrf2/HO-1 signaling in mediating the cardioprotective function of AST in CME. Conclusion: AST suppresses oxidative stress via activating Nrf2/HO-1 pathway and thus prevents CME-induced cardiomyocyte apoptosis and ameliorates cardiac dysfunction in rats.