Inhibition of gene expression of heart fatty acid binding protein and organic cation/carnitine transporter in doxorubicin cardiomyopathic rat model.
This study examined whether doxorubicin therapy alters the expression of heart fatty acid binding protein (H-FABP) and organic cation/carnitine transporter (OCTN2) genes in cardiac tissues, and if so, whether these alterations contributes to doxorubicin-induced cardiotoxicity. Male Wistar albino rats were divided into six groups: group 1 rats were given daily intraperitoneal (i.p.) injections of normal saline for 10 consecutive days; groups 2, 3 and 4 rats were injected every other day with doxorubicin (3 mg/kg, i.p.), to obtain treatments with cumulative doses of 6, 12, and 18 mg/kg. Rats in the fifth group were injected with L-carnitine (200 mg/kg, i.p.) for 10 consecutive days. Animals in the sixth group received doxorubicin (18 mg/kg) and L-carnitine (200 mg/kg). Treatment with doxorubicin resulted in a significant and dose-dependent decrease in H-FABP and OCTN2 mRNA expression, total carnitine and ATP in cardiac tissues and a significant increase in cardiac enzymes. Moreover, doxorubicin treatment showed significant and dose-dependent increase in the expression of apoptotic genes namely P53 and CD95. Interestingly, carnitine supplementation restored doxorubicin-induced inhibition of gene expression of H-FABP and OCTN2, decrease in myocardial carnitine and ATP to the control values. In conclusion, data from this study suggest that: chronic doxorubicin therapy decreased the expression of H-FABP and OCTN2 mRNA expression in cardiac tissues. The progressive increase in cardiotoxicity enzymatic indices and the decrease in H-FABP and OCTN2 expression may point to the possible contribution of H-FABP and OCTN2 as a mechanism during development of doxorubicin cardiotoxicity.
Sayed-Ahmed
Mohamed M
MM
Department of Pharmacology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia. mmsayedahmed@hotmail.com
Al-Shabanah
Othman A
OA
Hafez
Mohamed M
MM
Aleisa
Abdulaziz M
AM
Al-Rejaie
Salem S
SS
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000235:genetics*; D054715:Cardiotoxins / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006321:Heart / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D000074058:Solute Carrier Family 22 Member 5; D013997:Time Factors
D054715:Cardiotoxins; D050556:Fatty Acid-Binding Proteins; D027701:Organic Cation Transport Proteins; C115441:Slc22a5 protein, rat; D000074058:Solute Carrier Family 22 Member 5; D004317:Doxorubicin