Abstract 1605: T-Type Calcium Current Activates Pro-Survival Signaling Pathways after Myocardial Infarction
Ca2+ influx through L-type Ca2+ channels (ICa,L) is essential for cardiac contraction and for activation of a variety of Ca2+ dependent signaling pathways. However, Ca2+ can also enter cardiac myocytes through T-type Ca2+ channels (TTCCs), which are found in the fetal heart and become re-expressed in adult ventricular myocytes (VMs) during cardiac pathology. While excess ICa,L promotes VM death and dysfunction, the role of Ca2+ influx through TTCCs (ICa,T) in cardiac stress responses is unknown and is the topic of this study.
METHODS: Transgenic (TG) mice with inducible, cardiac-specific expression of α1G-TTCCs and control (CTR) mice were used. Myocardial infarction (MI) was induced by permanent ligation of the left anterior descending coronary artery. Mice were sacrificed at 1 week and 7 weeks post-MI.
RESULTS: TG hearts had greater in vivo fractional shortening (FS) than CTR (TG: 39.6±3.2%, N=16 vs CTR: 32.2±1.2%, N=14; p<0.05). VMs isolated from TG hearts showed peak ICa,T of −32.8±3.0 pA/pF. ICa,L was smaller in TG than in CTR VMs (−9.6±0.7 pA/pF vs −12.0±0.4 pA/pF, p< 0.05). Compared to ICa,L, ICa,T triggered smaller Ca2+ transients (1.5±0.1 vs 2.1±0.1, n=10; p<0.01) and contractions (2.6±0.7% vs 8.7±1.2%, n=10; p<0.01). Despite higher Ca2+ influx than CTR hearts, TG hearts showed no cardiac histopathology or premature death, and TG hearts had higher levels of phosphorylated Akt (p<0.05) and dephosphorylated NFAT (p<0.05), which are known to be cytoprotective. After 1 week of MI, TG and CTR hearts displayed similar reductions in FS (25.3±1.7%, N=14 vs 25.7±1.8%, N=19) and increases in cardiac size (HW/BW, mg/g: 4.4±0.1, N=14 vs 4.5±0.3, N=19). However, TG hearts had smaller infarcts than CTR hearts (19.9±1.8%, N=7 vs 28.4±2.3%, N=6, p<0.01). At 7 weeks post-MI, TG mice showed a higher survival rate than CTR mice (66.7% vs 47.6%). Also, at 7 weeks post-MI, TG hearts were larger than CTR (HW/BW: 10.4±1.0, N=12 vs 7.7±0.5, N=10; p<0.05) and had similar FS to CTR hearts (28.7±2.7, N=8 vs 28.0±2.8) and isolated VM contractility (TG: 5.6±0.7%, n=15 vs CTR: 5.3±0.5%, n=14).
CONCLUSION: Ca2+ influx via TTCCs has small effects on cardiac contraction, but is associated with reduced infarct size and increased survival, suggesting that it induces cytoprotective signaling.
This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).