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The Role of STIM1 in Hypertrophy-Related Contractile Dysfunction
Troupes, Constantine
Troupes, Constantine
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Thesis/Dissertation
Date
2016
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Biomedical Sciences
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http://dx.doi.org/10.34944/dspace/4126
Abstract
Increases in cardiac afterload caused by disease conditions results in remodeling of heart structure by hypertrophy and alterations in the molecular regulation of contractile performance. These adaptations can be regulated by various Ca2+-dependent signaling processes. STIM1 is an important regulator of Ca2+ signaling in different cell types by sensing endoplasmic reticular Ca2+ levels and coupling to plasma membrane Orai channels. The role of STIM1 in heart is not well understood, given the robust Ca2+ regulatory machinery present within cardiac myocytes. Previous reports indicate that STIM1 may play a role in regulation of cardiac hypertrophy. The goal of this work is to understand how STIM1 can affect contractile Ca2+ regulation in normal and diseased myocytes. We induced cardiac hypertrophy by slow progressive pressure overload in adult cats. Isolated adult feline ventricular myocytes (AFMs) exhibited increased STIM1 expression and activity, which correlated with altered Ca2+ handling. Use of BTP2 to block Orai channels resulted in a reduction of action potential (AP) duration and diastolic spark rate of hypertrophied myocytes, without affecting myocytes from sham-operated animals. Overexpressed STIM1 in cultured AFMs caused persistent Ca2+ influx that resulted in increased diastolic spark rates and prolonged APs, similar to myocytes from banded animals. STIM1 mediated Ca2+ influx could load the sarcoplasmic reticulum and activated CaMKII, which increased spark rates and lead to spontaneous APs. Importantly, STIM1 operated by associating with Orai channels because these effects could be blocked with either BTP2 or with a dominant negative Orai construct. Prolonged Ca2+ entry through this pathway eventually causes cell death. In conclusion, the work presented in this thesis establishes a role for STIM1-Orai in contractile Ca2+ regulation.
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