Premium
Inducible expression of active Inhibitor‐1 enhances cardiac function and improves contractility after an ischemic insult
Author(s) -
Nicolaou Persoulla A.,
Zhou Xiaoyang,
Rodriguez Patricia,
Mitton Bryan,
Pathak Anand,
Robbins Jeffrey,
Kranias Evangelia G.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.970.15
Subject(s) - contractility , phospholamban , cardiac function curve , medicine , in vivo , endocrinology , cardioprotection , ryanodine receptor , phosphorylation , ex vivo , ischemia , chemistry , biology , heart failure , microbiology and biotechnology , calcium
Inhibitor‐1 (I‐1) is a critical regulator of cardiac function. Upon phosphorylation at T35, I‐1 inhibits Protein Phosphatase‐1 (PP1) and augments contractility. In fact, the depressed function in failing hearts is partially attributed to impaired PP1 regulation via I‐1. To define any beneficial effects of acute I‐1 expression, we generated a double transgenic (DTG) mouse model with inducible (Tet‐off) expression of active I‐1 (T35D). 8 weeks of I‐1 expression elicited maximal stimulation on cardiac function, assessed by in vivo catheterization. Specifically, the contraction and relaxation rates were increased by 21% and 32% respectively, as compared to wild‐type. This was specifically attributed to increased phospholamban phosphorylation, while there were no changes in Troponin I and the Ryanodine Receptor. To examine the potential therapeutic role of I‐1 in ischemia/reperfusion (I/R), we subjected hearts to global I/R ex vivo . The DTG mice continued to show higher contractility (by 27%), which was not accompanied by altered necrotic injury, assessed by infarct size and LDH efflux. However, apoptotic injury was significantly attenuated in the DTG hearts. In conclusion , expression of I‐1 enhances basal contractility and improves functional recovery after an ischemic insult, suggesting that I‐1 may represent a potential therapeutic target in myocardial infarction. (NIH HL64018 to EGK, AHA 0715500B to PN)