title: Heme oxygenase-1 expression protects the heart from acute injury caused by inducible Cre recombinase.
abstract: The protective effect of heme oxygenase-1 (HO-1) expression in cardiovascular disease has been previously demonstrated using transgenic animal models in which HO-1 is constitutively overexpressed in the heart. However, the temporal requirements for protection by HO-1 induction relative to injury have not been investigated, but are essential to employ HO-1 as a therapeutic strategy in human cardiovascular disease states. Therefore, we generated mice with cardiac-specific, tamoxifen (TAM)-inducible overexpression of a human HO-1 (hHO-1) transgene (myosin heavy chain (MHC)-HO-1 mice) by breeding mice with cardiac-specific expression of a TAM-inducible Cre recombinase (MHC-Cre mice), with mice containing an hHO-1 transgene preceded by a floxed-stop signal. MHC-HO-1 mice overexpress HO-1 mRNA and the enzymatically active protein following TAM administration (40 mg/kg body weight on 2 consecutive days). In MHC-Cre controls, TAM administration leads to severe, acute cardiac toxicity, cardiomyocyte necrosis, and 80% mortality by day 3. This cardiac toxicity is accompanied by a significant increase in inflammatory cells in the heart that are predominantly neutrophils. In MHC-HO-1 mice, HO-1 overexpression ameliorates the depression of cardiac function and high mortality rate observed in MHC-Cre mice following TAM administration and attenuates cardiomyocyte necrosis and neutrophil infiltration. These results highlight that HO-1 induction is sufficient to prevent the depression of cardiac function observed in mice with TAM-inducible Cre recombinase expression by protecting the heart from necrosis and neutrophil infiltration. These findings are important because MHC-Cre mice are widely used in cardiovascular research despite the limitations imposed by Cre-induced cardiac toxicity, and also because inflammation is an important pathological component of many human cardiovascular diseases.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Travis D
authors.initials: TD
authors.lastname: Hull
authors.forename: Subhashini
authors.initials: S
authors.lastname: Bolisetty
authors.forename: Angela C
authors.initials: AC
authors.lastname: DeAlmeida
authors.forename: Silvio H
authors.initials: SH
authors.lastname: Litovsky
authors.forename: Sumanth D
authors.initials: SD
authors.lastname: Prabhu
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.forename: James F
authors.initials: JF
authors.lastname: George
mesh_terms: D000208:Acute Disease; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D004195:Disease Models, Animal; D004790:Enzyme Induction; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006331:Heart Diseases / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019426:Integrases / Q000096:biosynthesis* / Q000235:genetics; D008136:Longevity / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D009336:Necrosis / Q000139:chemically induced; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D015996:Survival Rate; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D051547:Heme Oxygenase-1; C045073:Cre recombinase; D019426:Integrases