| Autor: |
Badin J; ZOLL Medical Corporation, Chelmsford, MA, United States., Rodenbeck S; Department of Biology, Harding University, Searcy, AR, United States., McKenney-Drake ML; Butler University, Health Sciences Department, Pharmacy and Health Sciences, Indianapolis, IN, United States., Sturek M; Department of Anatomy, Cell Biology, & Physiology, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address: msturek@iu.edu. |
| Abstrakt: |
Ischemic heart disease due to macrovascular atherosclerosis and microvascular dysfunction is the major cause of death worldwide and the unabated increase in metabolic syndrome is a major reason why this will continue. Intracellular free Ca 2+ ([Ca 2+ ] i ) regulates a variety of cellular functions including contraction, proliferation, migration, and transcription. It follows that studies of vascular Ca 2+ regulation in reductionist models and translational animal models are vital to understanding vascular health and disease. Swine with metabolic syndrome (MetS) develop the full range of coronary atherosclerosis from mild to severe disease. Intravascular imaging enables quantitative measurement of atherosclerosis in vivo, so viable coronary smooth muscle (CSM) cells can be dispersed from the arteries to enable Ca 2+ transport studies in native cells. Transition of CSM from the contractile phenotype in the healthy swine to the proliferative phenotype in mild atherosclerosis was associated with increases in SERCA activity, sarcoplasmic reticulum Ca 2+ , and voltage-gated Ca 2+ channel function. In vitro organ culture confirmed that SERCA activation induces CSM proliferation. Transition from the proliferative to a more osteogenic phenotype was associated with decreases in all three Ca 2+ transporters. Overall, there was a biphasic change in Ca 2+ transporters over the progression of atherosclerosis in the swine model and this was confirmed in CSM from failing explanted hearts of humans. A major determinant of endolysosome content in human CSM is the severity of atherosclerosis. In swine CSM endolysosome Ca 2+ release occurred through the TPC2 channel. We propose a multiphasic change in Ca 2+ transporters over the progression of coronary atherosclerosis.
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