Higenamine Attenuates Doxorubicin-Induced Cardiac Remodeling and Myocyte Apoptosis by Suppressing AMPK Activation.

Background: As an effective antitumor drug, doxorubicin (DOX) is primarily used to treat solid tumors and hematologic malignancies. However, increasing evidence has emerged indicating its cardiotoxicity, and few solutions have been proposed to counter this side effect. Higenamine (HG) is a natural compound widely found in many Chinese herbs and also serves as a component in many healthcare products. Several studies have demonstrated its cardioprotective effect in different models, but little is known about the underlying influences of HG against myocardial damage from DOX-induced chronic cardiotoxicity. Methods and Results: C57BL/6 mice and neonatal rat ventricular cardiomyocytes (NRVMs) were used to evaluate the cardioprotective effect of HG against DOX-induced myocardial damage. In mice, DOX (intraperitoneally injected 5 mg/kg every 3 days for 4 weeks) significantly increased cardiomyocyte apoptosis, cardiac atrophy, and cardiac dysfunction, which were significantly attenuated by HG (intragastrically administered with 10 mg/kg every day for 4 weeks). In NRVMs, DOX (3 µM for 24 h) significantly increased cell apoptosis and the level of reactive oxygen species while reducing the level of superoxide dismutase and mitochondrial membrane potential. Remarkably, HG can reverse these pathological changes caused by DOX. Interestingly, the protective effect of HG on DOX-induced cardiotoxicity was independent of the activation of the beta-2 adrenergic receptor (ß2-AR), known for mediating the effect of HG on antagonizing ischemia/reperfusion-induced cardiac apoptosis. Furthermore, HG attenuated the abnormal activation of phosphorylated adenosine-activated protein kinase (AMPK). Consistently, AMPK agonists (AICAR) can eliminate these pharmacological actions of HG. Conclusion: Collectively, our results suggested that HG alleviated DOX-induced chronic myocardial injury by suppressing AMPK activation and ROS production.

Galanthamine improves myocardial ischemia-reperfusion-induced cardiac dysfunction, endoplasmic reticulum stress-related apoptosis, and myocardial fibrosis by suppressing AMPK/Nrf2 pathway in rats.

BACKGROUND: Myocardial ischemia/reperfusion (I/R) injury is an important cause of myocardial infarction and heart failure after cardiovascular surgery. Galanthamine (Gal) is an important Amaryllidaceae alkaloid with anti-acetylcholinesterase and anti-inflammatory activity. The purpose of this study was to investigate the role of Gal in myocardial I/R injury. METHODS: In this study, an animal model of myocardial I/R injury was constructed, and the rats were divided into five groups (n=10): the sham, I/R model, I/R + Gal (1 mg/kg), I/R + Gal (3 mg/kg), and I/R + Aspirin (20 mg/kg) groups. The expression of related proteins was detected by Western blotting and Immunohistochemistry, and Histological lesion was detected by HE staining. RESULTS: Results showed that Gal improves I/R-induced cardiac dysfunction in rats. Moreover, Gal inhibits I/R-induced endoplasmic reticulum stress (ERS)-related apoptosis by suppressing the expression of CHOP, Cleaved caspase 12, and caspase 3, and promoting the expression of CADD34 and BiP in rats. Furthermore, Gal mitigates I/R-induced myocardial fibrosis through restraining the expression of α-SMA and Collagen I in rats. Mechanically, Gal promoted the expression of AMPKα1, Nrf2 and HO-1. However, AMPK inhibitor Compound C exhibited the opposite effects. Collectively, this finding suggests that Gal improves I/R-induced cardiac dysfunction, ERS-related apoptosis, and myocardial fibrosis by activating AMPK/Nrf2 pathway in myocardial I/R rats. CONCLUSIONS: Given this evidence, Gal may be a potential therapeutic drug for the treatment of I/R injury.

Protective effect of metformin on H9C2 rat myocardial cell damage induced by saturated fatty acid / 重庆医学

Objective To investigate the mechanisms of metformin (Met) for protecting H9C2 myocardial cells damage induced by saturated fatty acids (palmitic acid,PA) in rats.Methods Rat H9C2 myocardial cell lines in blank control group,PA group and three different concentrations of metformin and PA combination groups were cultured for 24 h.Then Western blot was adopted to detect the protein expression of nuclear factor κB p65 (NFκB p65),intercellular cell adhesion molecule-1 (ICAM1),phosphorylated inhibitor of nuclear factor κB (p-IκBα) and phosphorylated adenosine monophosphate activated protein kinase(p-AMPK);the quantitative real-time PCR(qRT-PCR) was used to detect the mRNA expression of nuclear factor of nuclear factor κB(NFκB),chemokine (C-C motif) ligand 2 (CCL2) andintercellular cell adhesion molecule-1(ICAM1).Results Compared with the control groups,the protein expression of NFκB p65,p-IκBα and ICAM1 in the PA group was increased (P<0.05);compared with the PA group,the protein expression of NFκB p65,IκBα and ICAM1 in the Met+PA combination groups was decreased in various degrees with the Met concentration increase (all P<0.05),while the protein expression of p-AMPK was significantly risen with the Met concentration increase (all P<0.05).Compared with the control group,the mRNA expression of CCL2 and ICAM1 in the PA group was increased (P<0.05);compared with the PA group,the mRNA expression of CCL2 and ICAM1 in the Met+PA combination groups was decreased (P<0.05).Conclusion Met can alleviate H9C2 myocardial cellular damage caused by saturated fatty acid inducing increase of CCL2 and ICAM1 expression.

Possible involvement of AMPK in acute exercise-induced expression of monocarboxylate transporters MCT1 and MCT4 mRNA in fast-twitch skeletal muscle.

OBJECTIVE: The regulatory mechanisms responsible for acute exercise-induced expression of monocarboxylate transporters MCT1 and MCT4 mRNA in skeletal muscle remain unclear. 5'-adenosine-activated protein kinase (AMPK) is a key signaling molecule that regulates gene expression at the mRNA level. We examined whether AMPK activation is involved in acute exercise-induced expression of MCT1 and MCT4 mRNA in fast-twitch muscle. MATERIALS/METHODS: Male Sprague-Dawley rats were subjected to an acute bout of either 5min high-intensity intermittent swimming (HIS) or 6-h low-intensity prolonged swimming (LIS). The effects of acute exercise on the phosphorylation of AMPK (p-AMPK), calcium/calmodulin pendent kinase II (p-CaMKII), p38 mitogen-activated protein kinase (p-p38MAPK), and MCTs mRNA were analyzed in vivo. To observe the direct effects of AMPK activation on MCTs mRNA, the effects of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), caffeine, and dantrolene were analyzed in vitro using an isolated muscle incubation model. RESULTS: The p-AMPK increased in response to both HIS and LIS, although the p-CaMKII and p-p38MAPK were increased only following HIS. Irrespective of exercise intensity, MCT1 and MCT4 mRNA was also transiently upregulated by both HIS and LIS. Direct exposure of the epitrochlearis muscle to 0.5mmol/L AICAR or 1mmol/L caffeine, which activated p-AMPK increased both MCT1 and MCT4 mRNA levels. When pAMPK was inhibited by dantrolene, neither MCT1 nor MCT4 mRNA was increased. CONCLUSION: These results suggest that acute exercise-induced increases in MCT1 and MCT4 mRNA expression may be possibly mediated by AMPK activation, at least in part in fast-twitch muscle.