Icariin attenuates excessive alcohol consumption-induced susceptibility to atrial fibrillation through SIRT3 signaling.

Excessive alcohol consumption has long been identified as a risk factor for adverse atrial remodeling and atrial fibrillation (AF). Icariin is a principal active component from traditional Chinese medicine Herba Epimedii and has been demonstrated to exert potential antiarrhythmic effect. The present study was designed to evaluate the effect of icariin against alcohol-induced atrial remodeling and disruption of mitochondrial dynamics and furthermore, to elucidate the underlying mechanisms. Excessive alcohol-treated C57BL/6 J mice were infected with serotype 9 adeno-associated virus (AAV9) carrying mouse SIRT3 gene or negative control virus. Meanwhile, icariin (50 mg/kg/d) was administered to the animals in the presence or absence of AAV9 carrying SIRT3 shRNA. We noted that 8 weeks of icariin treatment effectively attenuated alcohol consumption-induced atrial structural and electrical remodeling as evidenced by reduced AF inducibility and reversed atrial electrical conduction pattern as well as atrial enlargement. Furthermore, icariin-treated group exhibited significantly enhanced atrial SIRT3-AMPK signaling, decreased atrial mitoSOX fluorescence and mitochondrial fission markers, elevated mitochondrial fusion markers (MFN1, MFN2) as well as NRF-1-Tfam-mediated mitochondrial biogenesis. Importantly, these beneficial effects were mimicked by SIRT3 overexpression while abolished by SIRT3 knockdown. These data revealed that targeting atrial SIRT3-AMPK signaling and preserving mitochondrial dynamics might serve as the novel therapeutic strategy against alcohol-induced AF genesis. Additionally, icariin ameliorated atrial remodeling and mitochondrial dysfunction by activating SIRT3-AMPK signaling, highlighting the use of icariin as a promising antiarrhythmic agent in this circumstance.

Activation of PKG-CREB-KLF15 by melatonin attenuates Angiotensin II-induced vulnerability to atrial fibrillation via enhancing branched-chain amino acids catabolism.

Mitochondrial reactive oxygen species (ROS) damage and atrial remodeling serve as the crucial substrates for the genesis of atrial fibrillation (AF). Branched-chain amino acids (BCAAs) catabolic defect plays critical roles in multiple cardiovascular diseases. However, the alteration of atrial BCAA catabolism and its role in AF remain largely unknown. This study aimed to explore the role of BCAA catabolism in the pathogenesis of AF and to further evaluate the therapeutic effect of melatonin with a focus on protein kinase G (PKG)-cAMP response element binding protein (CREB)-Krüppel-like factor 15 (KLF15) signaling. We found that angiotensin II-treated atria exhibited significantly elevated BCAA level, reduced BCAA catabolic enzyme activity, increased AF vulnerability, aggravated atrial electrical and structural remodeling, and enhanced mitochondrial ROS damage. These deleterious effects were attenuated by melatonin co-administration while exacerbated by BCAA oral supplementation. Melatonin treatment ameliorated BCAA-induced atrial damage and reversed BCAA-induced down-regulation of atrial PKGIα expression, CREB phosphorylation as well as KLF15 expression. However, inhibition of PKG partly abolished melatonin-induced beneficial actions. In summary, these data demonstrated that atrial BCAA catabolic defect contributed to the pathogenesis of AF by aggravating tissue fibrosis and mitochondrial ROS damage. Melatonin treatment ameliorated Ang II-induced atrial structural as well as electrical remodeling by activating PKG-CREB-KLF15. The present study reveals additional mechanisms contributing to AF genesis and highlights the opportunity of a novel therapy for AF by targeting BCAA catabolism. Melatonin may serve as a potential therapeutic agent for AF intervention.

Naringenin Attenuates Myocardial Ischemia-Reperfusion Injury via cGMP-PKGIα Signaling and In Vivo and In Vitro Studies.

Endoplasmic reticulum (ER) stress and oxidative stress contribute greatly to myocardial ischemia-reperfusion (MI/R) injury. Naringenin, a flavonoid derived from the citrus genus, exerts cardioprotective effects. However, the effects of naringenin on ER stress as well as oxidative stress under MI/R condition and the detailed mechanisms remain poorly defined. This study investigated the protective effect of naringenin on MI/R-injured heart with a focus on cyclic guanosine monophosphate- (cGMP-) dependent protein kinase (PKG) signaling. Sprague-Dawley rats were treated with naringenin (50 mg/kg/d) and subjected to MI/R surgery with or without KT5823 (2 mg/kg, a selective inhibitor of PKG) cotreatment. Cellular experiment was conducted on H9c2 cardiomyoblasts subjected to simulated ischemia-reperfusion treatment. Before the treatment, the cells were incubated with naringenin (80 µmol/L). PKGIα siRNA was employed to inhibit PKG signaling. Our in vivo and in vitro data showed that naringenin effectively improved heart function while it attenuated myocardial apoptosis and infarction. Furthermore, pretreatment with naringenin suppressed MI/R-induced oxidative stress as well as ER stress as evidenced by decreased superoxide generation, myocardial MDA level, gp91 phox expression, and phosphorylation of PERK, IRE1α, and EIF2α as well as reduced ATF6 and CHOP. Importantly, naringenin significantly activated myocardial cGMP-PKGIα signaling while inhibition of PKG signaling with KT5823 (in vivo) or siRNA (in vitro) not only abolished these actions but also blunted naringenin's inhibitory effects against oxidative stress and ER stress. In summary, our study demonstrates that naringenin treatment protects against MI/R injury by reducing oxidative stress and ER stress via cGMP-PKGIα signaling. Its cardioprotective effect deserves further clinical study.

[The protective effect of Rhadiola Astragalus Codonopsis compound on myocardium in early stage of severe burn at plateau in rats].

OBJECTIVE: To investigate the severity of early myocardial injury in rats with 30% full thickness burn at plateau and the protective effects of Rhadiola Astragalus Codonopsis Compound (RACC) on the rat myocardial injury. METHODS: One hundred and four Wistar rats with 30% full thickness burn were randomly divided into RACC application (R, n = 48) and scalding group 1 (S, n = 48), and another 8 healthy Wistar rats as control group 2 (C, n = 8). Four ml of RACC was garaged into the rat stomach in R and 4 ml isotonic saline in S groups respectively, but no treatment in C group. Blood samples from the aorta were harvested in 3, 6, 12, 24, 48 and 72 postburn hours (PBH) for blood gas analysis and for the determination of the changes in myocardial enzymes. Rat heart was harvested for pathomorphological examination. RESULTS: The rat myocardial tissue injury in R and S groups was obvious at 3 PBH and ameliorated gradually thereafter, up to the degree in C group at 72 PBH. The serum levels of myocardial enzymes in R and S groups were significantly higher than those in C group (P < 0.01). Whereas the enzymes in R group were much lower than those in S group (P < 0.01). It was indicated by blood gas analysis that the pH in R and S groups was lower than that in C group (P < 0.05), while that in R group at 12 - 24 PBH was higher than that in S group (P < 0.05). In addition, the base excess in R and S groups was lower than that in C group (P < 0.01), while that in R group at 6 PBH was higher than that in S group (P < 0.05 approximately 0.01). The PaCO2 in R and S groups was evidently lower than that in C group (P < 0.05 approximately 0.01), while that in R group at 48 PBH was no different to that in C group (35.70 +/- 4.23 mmHg vs 37.50 +/- 6.53 mmHg, P > 0.05). The PaO2 in R and S groups at 3 approximately 24 PBH was higher than that in C group and decreased gradually (P > 0.05). There was no difference in SaO2 among 3 groups (P > 0.05). CONCLUSION: RACC exhibited beneficial to the protection of rat heart from myocardial injury at plateau induced by severe burn.