title: Differential cardiotoxicity in response to chronic doxorubicin treatment in male spontaneous hypertension-heart failure (SHHF), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats.
abstract: 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 12weeks 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.
authors.affiliation: Veterinary Clinical Sciences Department, University of Minnesota, 1352 Boyd Ave, St. Paul, MN 55108 USA. Electronic address: shark009@umn.edu.
authors.forename: Leslie C
authors.initials: LC
authors.lastname: Sharkey
authors.forename: M Judith
authors.initials: MJ
authors.lastname: Radin
authors.forename: Lois
authors.initials: L
authors.lastname: Heller
authors.forename: Lynette K
authors.initials: LK
authors.lastname: Rogers
authors.forename: Anthony
authors.initials: A
authors.lastname: Tobias
authors.forename: Ilze
authors.initials: I
authors.lastname: Matise
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.forename: Fred S
authors.initials: FS
authors.lastname: Apple
authors.forename: Sylvia A
authors.initials: SA
authors.lastname: McCune
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000097:blood; D000818:Animals; D016718:Arachidonic Acid / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D054715:Cardiotoxins / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000633:toxicity*; D004851:Epoxide Hydrolases / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006331:Heart Diseases / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D017998:Leukotriene D4 / Q000097:blood; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020107:Troponin T / Q000097:blood; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D054715:Cardiotoxins; D020107:Troponin T; D016718:Arachidonic Acid; D017998:Leukotriene D4; D004317:Doxorubicin; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid
keywords: %FS; Arachidonic acid; BW; CYP; Cardiotoxicity; DHET; DOX; Doxorubicin; EET; Epoxyeicosatrienoic acid; HE; HETE; Hypertension; LTD4; LVIDd; LVIDs; SAL; SBP; SHHF; SHR; Soluble epoxide hydrolase; WKY; Wistar Kyoto rat; body weight; cTnT; cardiac troponin T; cytochrome P450; dihydroxyeicosatrienoic acid; doxorubicin; epoxyeicosatrienoic acid; hematoxylin and eosin; hydroxyeicosatetraenoic acid; left ventricular fractional shortening; left ventricular internal diameter in diastole; left ventricular internal diameter in systole; leukotriene D4; sEH; saline; soluble epoxide hydrolase; spontaneous hypertension heart failure rat; spontaneously hypertensive rat; systolic blood pressure