Characterization of Stressed Transgenic Mice Overexpressing H-Histamine Receptors in the Heart.

We studied transgenic mice with cardiac-specific overexpression of H-histamine receptors (H-TG) by using the -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 high histamine concentrations. Moreover, we assessed cardiac function using echocardiography in mice with cardiac hypertrophy due to overexpression of the catalytic subunit of PP2A (PP2A-TG) in the heart [H-TG × PP2A-TG = double transgenic (DT)] or H-TG with cardiac systolic failure due to treatment of mice with lipopolysaccharides (LPSs). Furthermore, the effect of ischemia and reperfusion was studied in isolated perfused hearts (Langendorff mode) of H-TG. We detected evidence for the protective role of the overexpressed H-histamine receptors in the contractile dysfunction of DT and isolated atrial preparations subjected to hypoxia. In contrast, we noted the detrimental role of H-histamine receptor overexpression against ischemia (Langendorff perfusion) and LPS-induced systolic heart failure. Hence, the role of H-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 H-histamine receptor overexpression in the mammalian heart remain to be elucidated. SIGNIFICANCE STATEMENT: The beneficial and detrimental effects of the cardiac effects of H-histamine receptors in the heart under stressful conditions, here intended to mimic clinical situations, were studied. The data suggest that depending on the clinically underlying cardiac pathophysiological mechanisms, H-histamine agonists or H-histamine antagonists might merit further research efforts to improve clinical drug therapy.