oxadin and Cardiomyopathies

Doxorubicin (DOX) is a highly effective anticancer anthracycline drug, but its side effects at the level of the heart has limited its widespread clinical application. Melatonin is a documented potent antioxidant, nontoxic and cardioprotective agent, and it is involved in maintaining mitochondrial homeostasis and function. The present study established acute DOX-induced cardiotoxicity models in both H9c2 cells incubated with 1 μM DOX and C57BL/6 mice treated with DOX (20 mg/kg cumulative dose). Melatonin markedly alleviated the DOX-induced acute cardiac dysfunction and myocardial injury. Both in vivo and in vitro studies verified that melatonin inhibited DOX-induced mitochondrial dysfunction and morphological disorders, apoptosis, and oxidative stress via the activation of AMPK and upregulation of PGC1α with its downstream signaling (NRF1, TFAM and UCP2). These effects were reversed by the use of AMPK siRNA or PGC1α siRNA in H9c2 cells, and were also negated by the cotreatment with AMPK inhibitor Compound C in vivo. Moreover, PGC1α knockdown was without effect on the AMPK phosphorylation induced by melatonin in the DOX treated H9c2 cells. Therefore, AMPK/PGC1α pathway activation may represent a new mechanism for melatonin exerted protection against acute DOX cardiotoxicity through preservation of mitochondrial homeostasis and alleviation of oxidative stress and apoptosis.

Topics: AMP-Activated Protein Kinases; Animals; Antibiotics, Antineoplastic; Apoptosis; Cardiomyopathies; Cardiotonic Agents; Cardiotoxicity; Cell Line; DNA-Binding Proteins; Doxorubicin; Gene Expression Regulation; High Mobility Group Proteins; Male; Melatonin; Mice; Mice, Inbred C57BL; Mitochondria; Myocytes, Cardiac; Nuclear Respiratory Factor 1; Oxazines; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphorylation; Rats; RNA, Small Interfering; Signal Transduction; Uncoupling Protein 2

Leukotriene B4 (LTB4)-mediated leukocyte recruitment and inflammatory cytokine production make crucial contributions to chronic inflammation and sepsis; however, the role of LTB4 in lipopolysaccharide (LPS)-induced cardiac dysfunction remains unclear. Therefore, the present study addressed this issue using an LTB4 receptor 1 (BLT1) inhibitor. Administration of LPS to mice resulted in decreased cardiovascular function. Inhibition of LTB4/BLT1 with the BLT1 inhibitor U75302 significantly improved survival and attenuated the LPS-induced acute cardiac dysfunction. During LPS challenge, the phosphorylated AMPK/ACC signaling pathway was slightly activated, and this effect was enhanced by U75302. Additionally, pNF-κB, Bax and cleaved caspase-3 were upregulated by LPS, and Bcl-2, IκB-α, mitochondrial complex I, complex II, and OPA1 were downregulated; however, these effects were reversed by U75302. The results indicated that the BLT1 antagonist suppressed cardiac apoptosis, inflammation, and mitochondrial impairment. Furthermore, the protection provided by the BLT1 inhibitor against LPS-induced cardiac dysfunction was significantly reversed by the AMPK inhibitor Compound C. In conclusion, inhibiting the LTB4/BLT1 signaling pathway via AMPK activation is a potential treatment strategy for septic cardiac dysfunction because it efficiently attenuates cardiac apoptosis, which may occur via the inhibition of inflammation and mitochondrial dysfunction.

Topics: Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; bcl-2-Associated X Protein; Cardiomyopathies; Cardiotonic Agents; Caspase 3; Fatty Alcohols; Gene Expression Regulation; Glycols; I-kappa B Proteins; Inflammation; Leukotriene B4; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mitochondria; NF-kappa B; Oxazines; Proto-Oncogene Proteins c-bcl-2; Receptors, Leukotriene B4; Signal Transduction; Survival Analysis