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CARDIOVASCULAR
AND RENAL PHARMACOLOGY
JOEL S. KARLINER, M.D., Professor of Medicine, Cardiology
Dr. Karliner's laboratory has been devoted to studies of signaling pathways in cardiac myocytes principally mediated by adrenoceptors and the effects on these pathways of acute and chronic hypoxia. In recent in vitro studies, he has used a model of chronic hypoxia in neonatal rat ventricular myocytes. These investigations showed that under normoxic conditions a 1-adrenoceptor mRNA subtypes are differentially regulated by hypertrophic stimuli, and that chronic hypoxia reverses this differential regulation and inhibits a 1-adrenoceptor-stimulated cardiac hypertrophy and signaling. He has also shown that chronic hypoxia modulates the interleukin-1b pathway by abolishing IL-1b -stimulated NO production and NF-k B activation, and reduces iNOS protein and mRNA levels. Chronic hypoxia also augments b -adrenoceptor density and mRNA but not signaling. In cardiac fibroblasts he has also shown that IL-1b stimulates ICAM mRNA but not protein during acute hypoxia.
His laboratory has recently identified unusual inhibitory receptor crosstalk between two molecules that stimulate cardiac hypertrophy. It was found that angiotensin (Ang) II downregulates a 1a mRNA and receptor number, as well as norepinephrine-stimulated early gene responses in cardiac myocytes. He has also probed the mechanism whereby Ang II stimulates cardiac myocyte hypertrophy and found that contrary to most assumptions, cardiac myocytes do not contain receptors for Ang II, either by autoradiography, antibody studies, or radioligand binding, and that Ang II mRNA in myocyte cultures can be accounted for by contaminating nonmyocytes. The Ang II receptors are found exclusively on the cardiac fibroblasts, and two of the pathways by which Ang II stimulates cardiac hypertrophy involve paracrine release of endothelin and TGFb . Since Ang II is known to cause release of endothelin from cardiac fibroblasts, these observations suggest that the major effects of Ang II on cardiac myocytes are indirect. Current studies are focused on cardiac fibroblast responses to endothelin-1 and interleukin-1b . Another focus of study is the role of protein kinase C isozymes in the mechanism of hypoxic preconditioning in cardiac myocytes.
SELECTED PUBLICATIONS:
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