This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 104/8/1012    most recent CIRCRESAHA.108.189811v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nicolaou, P. Articles by Kranias, E. G. Search for Related Content PubMed PubMed Citation Articles by Nicolaou, P. Articles by Kranias, E. G. Related Collections Calcium cycling/excitation-contraction coupling Ischemic biology - basic studies

(Circulation Research. 2009;104:1012.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Inducible Expression of Active Protein Phosphatase-1 Inhibitor-1 Enhances Basal Cardiac Function and Protects Against Ischemia/Reperfusion Injury

Persoulla Nicolaou, Patricia Rodriguez, Xiaoping Ren, Xiaoyang Zhou, Jiang Qian, Sakthivel Sadayappan, Bryan Mitton, Anand Pathak, Jeffrey Robbins, Roger J. Hajjar, Keith Jones, Evangelia G. Kranias

From the Department of Pharmacology and Cell Biophysics (P.N., P.R., X.R., X.Z., J.Q., B.M., A.P., K.J., E.G.K.), University of Cincinnati College of Medicine, Ohio; Division of Molecular Cardiovascular Biology (S.S., J.R.), Cincinnati Children’s Hospital Research Foundation, Ohio; Cardiovascular Research Center (R.J.H.), Mount Sinai School of Medicine, New York, NY; and Foundation for Biomedical Research of the Academy of Athens (E.G.K.), Greece.

Correspondence to Evangelia G. Kranias, Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267-0575. E-mail Litsa.Kranias{at}uc.edu

Ischemic heart disease, which remains the leading cause of morbidity and mortality in the Western world, is invariably characterized by impaired cardiac function and disturbed Ca²⁺ homeostasis. Because enhanced inhibitor-1 (I-1) activity has been suggested to preserve Ca²⁺ cycling, we sought to define whether increases in I-1 activity in the adult heart may ameliorate contractile dysfunction and cellular injury in the face of an ischemic insult. To this end, we generated an inducible transgenic mouse model that enabled temporally controlled expression of active I-1 (T35D). Active I-1 expression in the adult heart elicited significant enhancement of contractile function, associated with preferential phospholamban phosphorylation and enhanced sarcoplasmic reticulum Ca²⁺-transport. Further phosphoproteomic analysis revealed alterations in proteins associated with energy production and protein synthesis, possibly to support the increased metabolic demands of the hyperdynamic hearts. Importantly, on ischemia/reperfusion-induced injury, active I-1 expression augmented contractile function and recovery. Further examination revealed that the infarct region and apoptotic as well as necrotic injuries were significantly attenuated by enhanced I-1 activity. These cardioprotective effects were associated with suppression of the endoplasmic reticulum stress response. The present findings indicate that increased I-1 activity in the adult heart enhances Ca²⁺ cycling and improves mechanical recovery, as well as cell survival after an ischemic insult, suggesting that active I-1 may represent a potential therapeutic strategy in myocardial infarction.

Key Words: ischemia • reperfusion • protein phosphatase-1 inhibitor-1 • phospholamban • ER stress

This article has been cited by other articles:

				J. Qian, X. Ren, X. Wang, P. Zhang, W. K. Jones, J. D. Molkentin, G.-C. Fan, and E. G. Kranias Blockade of Hsp20 Phosphorylation Exacerbates Cardiac Ischemia/Reperfusion Injury by Suppressed Autophagy and Increased Cell Death Circ. Res., December 4, 2009; 105(12): 1223 - 1231. [Abstract] [Full Text] [PDF]