Carnitine Supplementation Attenuates Sunitinib-Induced Inhibition of AMP-Activated Protein Kinase Downstream Signals in Cardiac Tissues

Autor: Mashan L. Abdullah, Ammar C. Al-Rikabi, Badr I. Alrufaiq, Othman A. Al-Shabanah, Mohamed M. Sayed-Ahmed, Mohamed M. Hafez
Rok vydání: 2019
Předmět:
Male
medicine.medical_specialty
Heart Diseases
CPT I
Antineoplastic Agents
030204 cardiovascular system & hematology
AMP-Activated Protein Kinases
Toxicology
Mitochondria
Heart
Article
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Adenosine Triphosphate
AMP-activated protein kinase
Internal medicine
Carnitine
medicine
Sunitinib
Animals
Myocytes
Cardiac
Rats
Wistar
Molecular Biology
Protein Kinase Inhibitors
Mitochondrial transport
Cardiotoxicity
biology
Carnitine O-Palmitoyltransferase
AMPK
Adenosine
l-carnitine
Malonyl Coenzyme A
Endocrinology
chemistry
030220 oncology & carcinogenesis
Dietary Supplements
biology.protein
Carnitine palmitoyltransferase I
Cardiology and Cardiovascular Medicine
Energy Metabolism
Adenosine triphosphate
medicine.drug
Acetyl-CoA Carboxylase
Signal Transduction
Zdroj: Cardiovascular Toxicology
ISSN: 1559-0259
Popis: This study has been initiated to investigate whether sunitinib (SUN) alters the expression of key genes engaged in mitochondrial transport and oxidation of long chain fatty acids (LCFA), and if so, whether these alterations should be viewed as a mechanism of SUN-induced cardiotoxicity, and to explore the molecular mechanisms whereby carnitine supplementation could attenuate SUN-induced cardiotoxicity. Adult male Wister albino rats were assigned to one of the four treatment groups: Rats in group 1 received no treatment but free access to tap water for 28 days. Rats in group 2 received l-carnitine (200 mg/kg/day) in drinking water for 28 days. Rats in group 3 received SUN (25 mg/kg/day) in drinking water for 28 days. Rats in group 4 received the same doses of l-carnitine and SUN in drinking water for 28 days. Treatment with SUN significantly increased heart weight, cardiac index, and cardiotoxicity enzymatic indices, as well as severe histopathological changes. Moreover, SUN significantly decreased level of adenosine monophosphate-activated protein kinase (AMPKα2), total carnitine, adenosine triphosphate (ATP) and carnitine palmitoyltransferase I (CPT I) expression and significantly increased acetyl-CoA carboxylase-2 (ACC2) expression and malonyl-CoA level in cardiac tissues. Interestingly, carnitine supplementation resulted in a complete reversal of all the biochemical, gene expression and histopathological changes-induced by SUN to the control values. In conclusion, data from this study suggest that SUN inhibits AMPK downstream signaling with the consequent inhibition of mitochondrial transport of LCFA and energy production in cardiac tissues. Carnitine supplementation attenuates SUN-induced cardiotoxicity.
Databáze: OpenAIRE
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