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lüll Heme oxygenase-1 expression protects the heart from acute injury caused by inducible Cre recombinase Hull TD; Bolisetty S; DeAlmeida AC; Litovsky SH; Prabhu SD; Agarwal A; George JFLab Invest 2013[Aug]; 93 (8): 868-79The 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.|Acute Disease[MESH]|Animals[MESH]|Antineoplastic Agents, Hormonal/pharmacology[MESH]|Disease Models, Animal[MESH]|Enzyme Induction[MESH]|Female[MESH]|Heart Diseases/enzymology/mortality/pathology/*prevention & control[MESH]|Heart/drug effects/physiopathology[MESH]|Heme Oxygenase-1/genetics/*metabolism[MESH]|Humans[MESH]|Integrases/*biosynthesis/genetics[MESH]|Longevity/drug effects[MESH]|Male[MESH]|Mice[MESH]|Mice, Transgenic[MESH]|Myocardium/*enzymology/pathology[MESH]|Myocytes, Cardiac/enzymology/pathology[MESH]|Necrosis/chemically induced[MESH]|Neutrophils/drug effects/pathology[MESH]|Survival Rate[MESH]|Tamoxifen/pharmacology[MESH] |