dorsomorphin and Fibrosis

Adiponectin (APN) has been reported to protect against ischaemia-reperfusion injury and hypertrophy. However, few reports have investigated the cardioprotective effects of APN in doxorubicin (DOX)-induced cardiomyopathy; therefore, we studied the cardioprotective mechanisms of APN in this model.. In an in vivo study, we quantified the cardiac pathohistology of C57BL/6 mice [wild-type (WT) mice], APN transgenic mice with high APN concentrations [APN transgenic sense (SE) mice], and those with reduced APN concentrations [APN transgenic antisense (AS) mice] after intraperitoneal injections of DOX (4 mg/kg) weekly for 6 weeks. The survival rate after 14 days was significantly increased in APN-SE mice (WT vs. APN-AS vs. APN-SE: 40 vs. 17 vs. 73%, P < 0.05). We assessed myocardial pathohistological changes and observed that fibrosis and apoptosis were significantly decreased in APN-SE mice compared with those of the other groups. We also assessed DOX-induced apoptotic mechanisms in vitro using cultured cardiomyocytes isolated from neonatal WT mice. The expression of adenosine monophosphate-activated protein kinase (AMPK) and anti-apoptotic factor Bcl-2 increased, but that of pro-apoptotic factor Bax decreased in cardiomyocytes treated with highly concentrated APN. The protective effects of APN were reversed by the addition of an AMPK inhibitor (dorsomorphin) to the culture medium.. These data suggest that APN improved cardiac function through anti-apoptotic effects by up-regulation of AMPK in DOX-induced cardiomyopathy in mice.

Topics: Adiponectin; AMP-Activated Protein Kinases; Animals; Antibiotics, Antineoplastic; Apoptosis; bcl-2-Associated X Protein; Cardiomyopathies; Cells, Cultured; Doxorubicin; Fibrosis; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria, Heart; Myocardium; Myocytes, Cardiac; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Receptors, Adiponectin; Time Factors; Up-Regulation

Some studies have shown that metformin activates AMP-activated protein kinase (AMPK) and has a potent cardioprotective effect against ischemia/reperfusion injury. Because AMPK also is activated in animal models of heart failure, we investigated whether metformin decreases cardiomyocyte apoptosis and attenuates the progression of heart failure in dogs.. Treatment with metformin (10 micromol/L) protected cultured cardiomyocytes from cell death during exposure to H2O2 (50 micromol/L) via AMPK activation, as shown by the MTT assay, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and flow cytometry. Continuous rapid ventricular pacing (230 bpm for 4 weeks) caused typical heart failure in dogs. Both left ventricular fractional shortening and left ventricular end-diastolic pressure were significantly improved in dogs treated with oral metformin at 100 mg x kg(-1) x d(-1) (n=8) (18.6+/-1.8% and 11.8+/-1.1 mm Hg, respectively) compared with dogs receiving vehicle (n=8) (9.6+/-0.7% and 22+/-0.9 mm Hg, respectively). Metformin also promoted phosphorylation of both AMPK and endothelial nitric oxide synthase, increased plasma nitric oxide levels, and improved insulin resistance. As a result of these effects, metformin decreased apoptosis and improved cardiac function in failing canine hearts. Interestingly, another AMPK activator (AICAR) had effects equivalent to those of metformin, suggesting the primary role of AMPK activation in reducing apoptosis and preventing heart failure.. Metformin attenuated oxidative stress-induced cardiomyocyte apoptosis and prevented the progression of heart failure in dogs, along with activation of AMPK. Therefore, metformin may be a potential new therapy for heart failure.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Animals; Apoptosis; Cardiotonic Agents; Cells, Cultured; Disease Progression; Dogs; Drug Evaluation, Preclinical; Fibrosis; Gene Expression Regulation; Heart Failure; Insulin Resistance; Metformin; Myocytes, Cardiac; Natriuretic Peptides; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Phosphorylation; Protein Processing, Post-Translational; Pyrazoles; Pyrimidines; Rats; Rats, Wistar; Ribonucleotides; Transforming Growth Factor beta1; Ultrasonography; Ventricular Dysfunction, Left