Characterization of stressed transgenic mice overexpressing H2-histamine receptors in the heart.

We studied transgenic mice with cardiac-specific overexpression of H2-histamine receptors (H2-TG) by using the alpha myosin heavy chain promoter. We wanted to address whether this overexpression would protect the heart against paradigmatic stressors. To this end, we studied isolated atrial preparations in an organ bath under normoxic and hypoxic conditions and after prolonged exposure to prolonged high histamine concentrations. Moreover, we assessed cardiac function using echocardiography in mice with cardiac hypertrophy because of overexpression of the catalytic subunit of PP2A (PP2A-TG) in the heart (H2-TGxPP2A-TG=DT) or H2-TG with cardiac systolic failure because of treatment of mice with lipopolysaccharides (LPS). Furthermore, the effect of ischemia and reperfusion were studied in isolated perfused hearts (Langendorff-mode) of H2-TG. We detected evidence for the protective role of the overexpressed H2-histamine receptors in the contractile dysfunction of double transgenic (DT) and isolated atrial preparations subjected to hypoxia. In contrast, we noted the detrimental role of H2-histamine receptor overexpression against ischemia (Langendorff perfusion) and LPS-induced systolic heart failure. Hence, the role of H2-histamine receptors in the heart is context sensitive: the results differ between hypoxia (in atrium) and ischemia (perfused whole heart) as well as between genetically induced hypertrophy (DT) and toxin-induced heart failure (LPS). The underlying molecular mechanisms for the protective or detrimental roles of H2-histamine receptor overexpression in the mammalian heart remain to be elucidated.