Abstract P074: Loss of Function of TRPC4 Protects Against Cardiac Dysfunction Progression After Myocardial Infarction
The source of Ca2+ to hypertrophic signaling after myocardial infarction (MI) is not clearly defined. Transient Receptor Potential Canonical (TRPC) channels could be an important source of hypertrophic Ca2+ after MI. The objective of this study was to determine if TRPC 4 is a major source of Ca2+ influx mediating cardiac dysfunction after MI.
Methods: Cardiac-specific transgenic mice that express a dominant-negative (dn) TRPC4 that reduces the activity of the TRPC1/4/5 subfamily of channels in the heart were used. MI was produced and in-vivo cardiac function was measured with ECHO. Myocytes were isolated and isoproterenol (ISO) effects on LTCC Current (ICa-L), fractional shortening (FS) and Ca2+transients were measured 6 weeks after MI.
Results: Baseline ejection fraction (EF) and fractional shortening (FS) were greater in (dn) TRPC4 vs. WT mice. Two weeks after MI, EF and FS were significantly decreased in all animals (WT: 37.1% and 18.2%; (dn) TRPC4: 41.7% and 20.5%), but there was no significant difference between WT and (dn) TRPC4 mice. Six weeks after MI, EF and FS were significant greater in (dn) TRPC4 compared with WT mice (WT: 37.4% and 18.2%; (dn) TRPC4: 52.2% and 27.4%). Heart weight and lung weight were significantly increased after 2 weeks MI, but there were significant lower heart and lung weight in (dn) TRPC4 vs. WT mice after 6 weeks MI. ICa-L [[Unsupported Character - Codename ­]]after 6 weeks MI was smaller than that in sham myocytes, and there was no significant difference between (dn) TRPC4 and WT myocytes. Contractions and Ca2+ transients were significantly greater in sham and post-MI (dn) TRPC4 vs. WT myocytes. ISO increased contractions and Ca2+ transients to a similar extent in all myocytes.
Conclusions: (dn) TRPC4 mice have greater baseline cardiac and myocyte function. While initial effects of MI were similar to control, there was improved function in these mice by 6 weeks. These results suggest that blocking TRPC4 after MI may reduce pathological cardiac remodeling.
- © 2011 by American Heart Association, Inc.