Cellular antioxidant systems response to mitochondrial oxidative stress induced by statins in skelton muscle of hypercholesterolemic mice

• Grant number: 14/11261-2
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2014
• End date: May 31, 2017
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Aníbal Eugênio Vercesi
• Grantee: Estela Natacha Brandt Busanello
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The safety of statins treatment in hypercholesterolemic patients (around 50 million in USA) is very well documented. However, these works indicate that about 10% of patients develop adverse effects in skeletal muscle and other tissues. The mechanisms of statins toxicity seems to be related to cell death mediated by mitochondrial dysfunction associated with alterations in calcium homeostasis, inhibition of ²-oxidation followed by oxidative stress. In this context, our group showed that incubation of statins with muscle biopsies inhibited mitochondrial respiration and increased reactive oxygen production. These alterations were ubiquinone (Co-Q10) sensitive that, besides being an important respiratory chain electron transporter, also displays a free radical scavenger action. These results may possibly explain both cytotoxicity and muscle pain presented by statin-treated patients. Despite previous works indicating that statins provokes mitochondrial oxidative stress, respiration impairment and cell death, most of these results were obtained from the addition of statins to tissues obtained from animals with normal LDL receptor (LDLr) expression. Thus, our aim is to better understand the mechanisms underlying skeletal muscle toxicity caused by statins in LDLr knockout mice (LDLr-/-), which is a human familial hypercholesterolemia mice model. For this purpouse, we will verify if mitochondrial oxidative stress would lead to a higher expression and activity of cellular antioxidant systems in LDLr-/- mice under statin treatment. In addition, we will analyze lipidome components to characterize possible biomarkers. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BUSANELLO, ESTELA N. B.; FIGUEIRA, TIAGO R.; MARQUES, ANA C.; NAVARRO, CLAUDIA D. C.; OLIVEIRA, HELENA C. F.; VERCESI, ANIBAL E.. Facilitation of Ca2+-induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment. Cell Biology International, v. 42, n. 6, SI, p. 742-746, JUN 2018. (06/59786-0, 11/50400-0, 14/11261-2, 13/07607-8)

BUSANELLO, ESTELA N. B.; MARQUES, ANA C.; LANDER, NOELIA; DE OLIVEIRA, DIOGO N.; CATHARINO, RODRIGO R.; OLIVEIRA, HELENA C. F.; VERCESI, ANIBAL E.. Pravastatin Chronic Treatment Sensitizes Hypercholesterolemic Mice Muscle to Mitochondrial Permeability Transition: Protection by Creatine or Coenzyme Q(10). FRONTIERS IN PHARMACOLOGY, v. 8, APR 5 2017. (14/00084-2, 14/11261-2, 14/08995-4, 13/07607-8, 11/50400-0)

BUSANELLO, ESTELA N. B.; FIGUEIRA, TIAGO R.; MARQUES, ANA C.; NAVARRO, CLAUDIA D. C.; OLIVEIRA, HELENA C. F.; VERCESI, ANIBAL E.. Facilitation of Ca2+-induced opening of the mitochondrial permeability transition pore either by nicotinamide nucleotide transhydrogenase deficiency or statins treatment. Cell Biology International, v. 42, n. 6, p. 5-pg., 2018-06-01. (11/50400-0, 06/59786-0, 14/11261-2, 13/07607-8)

VERCESI, ANIBAL E.; CASTILHO, ROGER F.; KOWALTOWSKI, ALICIA J.; DE OLIVEIRA, HELENA C. F.; DE SOUZA-PINTO, NADJA C.; FIGUEIRA, TIAGO R.; BUSANELLO, ESTELA N. B.. Mitochondrial calcium transport and the redox nature of the calcium-induced membrane permeability transition. Free Radical Biology and Medicine, v. 129, p. 1-24, DEC 2018. (17/17728-8, 11/50400-0, 06/59786-0, 14/11261-2, 13/07607-8)