Heme oxygenase-1 expression protects the heart from acute injury caused by inducible Cre recombinase.

Academic Article

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.
  • Published In

    Keywords

  • Acute Disease, Animals, Antineoplastic Agents, Hormonal, Disease Models, Animal, Enzyme Induction, Female, Heart, Heart Diseases, Heme Oxygenase-1, Humans, Integrases, Longevity, Male, Mice, Mice, Transgenic, Myocardium, Myocytes, Cardiac, Necrosis, Neutrophils, Survival Rate, Tamoxifen
  • Digital Object Identifier (doi)

    Authorlist

  • Hull TD; Bolisetty S; DeAlmeida AC; Litovsky SH; Prabhu SD; Agarwal A; George JF
  • Start Page

  • 868
  • End Page

  • 879
  • Volume

  • 93
  • Issue

  • 8