Abstract 16984: Role of Inositol 1,4,5-Triphosphate Receptor 2 in Post-Ischemic Heart Failure
Introduction: The type 2 inositol 1,4,5-triphosphate receptor (IP3R2) is the predominant isoform expressed in ventricular cardiomyocytes. IP3R2-mediated Ca2+ release has been proposed to participate in atrial arrhythmogenesis. However, its involvement in post-ischemic heart failure (HF) has not been elucidated.
Methods: To investigate whether myocardial IP3R2 plays a functional role in HF, we generated myocardial specific IP3R2 knock-out (KO) mice by crossing IP3R2flox/flox mice (obtained by opportunely placing loxP sequences flanking exon 3 of IP3R2 gene) with α-MHCCre mice.
Results: We confirmed cardiomyocyte-specific IP3R2 deletion in IP3R2flox/flox/α-MHCCre mice (hereafter referred to as KO) at mRNA and protein levels. The loss of IP3R2 in the heart does not result in embryonic lethality: KO mice survived to adulthood and we did not detect any morphological or functional defects in baseline conditions. Serial cardiac ultrasound analyses performed following coronary artery ligation revealed a significant amelioration in cardiac function post myocardial infarction (MI) in KO mice compared with flox littermates (p<.05, ANOVA rep. measures, n=5-8/group). No significant differences were detected by radiotelemetry in blood pressure. Hemodynamic studies performed post-MI confirmed the improved cardiac contractility (dP/dtmax,KO:6424±424; flox:5794±410 mmHg/s; p<.05, n=6/group). These data are further supported by increased IP3R2 levels detected in HF patients. A markedly reduced percentage of apoptotic cells after MI was revealed by TUNEL assay in cardiac sections from KO mice compared with flox controls, mirrored by an augmented caspase activity and a decreased calcineurin phosphatase activity (p<.05, n=7/group). Furthermore, we observed decreased interstitial cardiac fibrosis in failing hearts from KO mice compared with their flox littermates (p<.05, n=6/group). No obvious difference was noticed examining ultrastructural mitochondria morphology.
Conclusions: Taken together our results indicate that myocardial IP3R2 plays a crucial role in the pathophysiology of HF, participating via a mechanism involving the calcineurin pathway in the regulation of fibrosis and apoptosis during post-ischemic cardiac remodeling.
Author Disclosures: G. Santulli: None. B. Chen: None. F. Forrester: None. H. Wu: None. S. Reiken: None. A.R. Marks: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.