Differential cardiotoxicity in response to chronic doxorubicin treatment in male spontaneous hypertension-heart failure (SHHF), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats
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- 作者：Leslie C. Sharkey ; M. Judith Radin ; Lois Heller ; Lynette K. Rogers ; Anthony Tobias ; Ilze Matise ; Qi Wang ; Fred S. Apple ; Sylvia A. McCune
- 关键词：BW ; body weight ; cTnT ; cardiac troponin T ; CYP ; cytochrome P450 ; DHET ; dihydroxyeicosatrienoic acid ; DOX ; doxorubicin ; EET ; epoxyeicosatrienoic acid ; HE ; hematoxylin and eosin ; HETE ; hydroxyeicosatetraenoic acid ; LTD4 ; leukotriene D4 ; LVIDd ; left ventricular internal diameter in diastole ; LVIDs ; left ventricular internal diameter in systole ; %FS ; left ventricular fractional shortening ; SAL ; saline ; SBP ; systolic blood pressure ; sEH ; soluble epoxide hydrolase ; SHHF ; spontaneous hypertension heart
- 刊名：Toxicology and Applied Pharmacology
- 出版年：15 November, 2013
- 年：2013
- 卷：273
- 期：1
- 页码：47-57
- 全文大小：1547 K
文摘
Life threatening complications from chemotherapy occur frequently in cancer survivors, however little is known about genetic risk factors. We treated male normotensive rats (WKY) and strains with hypertension (SHR) and hypertension with cardiomyopathy (SHHF) with 8 weekly doses of doxorubicin (DOX) followed by 12 weeks of observation to test the hypothesis that genetic cardiovascular disease would worsen delayed cardiotoxicity. Compared with WKY, SHR demonstrated weight loss, decreased systolic blood pressure, increased kidney weights, greater cardiac and renal histopathologic lesions and greater mortality. SHHF showed growth restriction, increased kidney weights and renal histopathology but no effect on systolic blood pressure or mortality. SHHF had less severe cardiac lesions than SHR. We evaluated cardiac soluble epoxide hydrolase (sEH) content and arachidonic acid metabolites after acute DOX exposure as potential mediators of genetic risk. Before DOX, SHHF and SHR had significantly greater cardiac sEH and decreased epoxyeicosatrienoic acid (EET) (4 of 4 isomers in SHHF and 2 of 4 isomers in SHR) than WKY. After DOX, sEH was unchanged in all strains, but SHHF and SHR rats increased EETs to a level similar to WKY. Leukotriene D4 increased after treatment in SHR. Genetic predisposition to heart failure superimposed on genetic hypertension failed to generate greater toxicity compared with hypertension alone. The relative resistance of DOX-treated SHHF males to the cardiotoxic effects of DOX in the delayed phase despite progression of genetic disease was unexpected and a key finding. Strain differences in arachidonic acid metabolism may contribute to variation in response to DOX toxicity.