title: Metformin protects against doxorubicin-induced cardiotoxicity: involvement of the adiponectin cardiac system.
abstract: Doxorubicin has cardiotoxic effects that limit its clinical benefit in cancer patients. Metformin exerts cardioprotective actions via AMP-activated protein kinase (AMPK) and increases the expression of adiponectin and its receptors (adipoR1 and adipoR2) in skeletal muscle and adipose tissue, but its effect on cardiac tissue is still unknown. This work aimed to study whether metformin exerts any protective action against the cardiotoxicity of doxorubicin and whether the cardiac system of adiponectin is involved in any such action. The addition of doxorubicin (5μM) to adult mouse cardiomyocytes (HL-1 cell line) induced apoptosis, which was characterized by a loss of cell viability, activation of caspases, and fragmentation of the genetic material. Doxorubicin treatment also caused a decrease in the activity of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase. Pretreatment with metformin (4mM, 24h) provided protection against doxorubicin-induced damage. This pretreatment significantly increased cell viability, attenuated the activation of caspases and the fragmentation of genetic material, and restored the antioxidant activity. In addition, metformin up-regulated the expression of adiponectin and its receptors, adipoR1 and adipoR2, in cardiomyocytes. In contrast, silencing either adipoR1 or adipoR2 with siRNA inhibited the AMPK activation and the protective effects of metformin. Taken together, these results demonstrate that metformin protects cardiomyocytes from doxorubicin-induced damage and that the cardiac adiponectin system plays an important role in this protective action.
authors: Heart Failure Unit, Cardiology Department, University Hospital Virgen de la Arrixaca, 30120 Murcia, Spain.
authors: Mari C
authors: MC
authors: Asensio-López
authors: Antonio
authors: A
authors: Lax
authors: Domingo A
authors: DA
authors: Pascual-Figal
authors: Mariano
authors: M
authors: Valdés
authors: Jesús
authors: J
authors: Sánchez-Más
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D053938:DNA Fragmentation / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008687:Metformin / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D054419:Receptors, Adiponectin / Q000235:genetics / Q000378:metabolism
chemical_list: C475418:ADIPOR1 protein, human; C475420:ADIPOR2 protein, human; D052242:Adiponectin; D034741:RNA, Small Interfering; D054419:Receptors, Adiponectin; D004317:Doxorubicin; D008687:Metformin; D000263:Adenylate Kinase