Discipline: Biological Sciences
Subcategory: Physiology and Health
Shericia C. Campbell - Virginia State University
Co-Author(s): Michael J. Zeitz, Mira Tanenbaum, & James W. Smyth
Heart Disease is the leading cause of death in the United States, with cardiovascular disease accounting for 1 in 4 of all deaths. In order for each heartbeat to occur, billions of cardiac muscle cells must contract simultaneously. These synchronized contractions are made possible by a subcellular channel known as the gap junction, which propagates direct signals from one cell to another at intercalated discs between cells. The gap junction protein Connexin-43(Cx43) is expressed in the working myocardium. During heart disease, such as cardiac hypertrophy, our lab has found that cardiomyocytes initiate the integrated stress response (ISR) resulting in altered Cx43 expression and localization. Hypertrophic cardiomyocytes are enlarged and alterations in Cx43 regulation lead to arrhythmias. We hypothesized that blocking the ISR would rescue Cx43 gap junction formation and restore proper intercellular communication in diseased hearts. Hypertrophy was induced in the hearts of adult C57BL/6 mice over seven days by osmotic minipump delivered isoproterenol with or without the ISR inhibitor ISRIB. Hearts were snap frozen and cryosectioned for immunostaining and
analysis by confocal microscopy. ImageJ software was employed to measure localization of Cx43 at the intercalated disc based on colocalization with N-cadherin and cell size. ISRIB treatment prevented pathological cell size increases while preserving more normal Cx43 expression. We are currently employing super-resolution microscopy to further define changes in cell junctions. Our data identify blocking the cellular stress response and preserving normal protein translation as a viable therapeutic avenue in preventing the arrhythmogenic pathological remodeling of cardiac gap junctions.
Funder Acknowledgement(s): NIH NHLBI R01 HC 132236
Faculty Advisor: James W. Smyth, email@example.com
Role: I did the data analysis of the cryosectioned mice hearts, and used a software to analyze the amount of Cx 43, and N-Cadherin.