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

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

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 Ca 2+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.

Original languageEnglish
Pages (from-to)1012-1020
Number of pages9
JournalCirculation Research
Volume104
Issue number8
DOIs
Publication statusPublished - 24 Apr 2009

Keywords

  • ER stress
  • Ischemia
  • Phospholamban
  • Protein phosphatase-1 inhibitor-1
  • Reperfusion

Fingerprint Dive into the research topics of 'Inducible Expression of Active Protein Phosphatase-1 Inhibitor-1 Enhances Basal Cardiac Function and Protects Against Ischemia/Reperfusion Injury'. Together they form a unique fingerprint.

  • Cite this

    Nicolaou, P., Rodriguez, P., Ren, X., Zhou, X., Qian, J., Sadayappan, S., Mitton, B., Pathak, A., Robbins, J., Hajjar, R. J., Jones, K., & Kranias, E. G. (2009). Inducible Expression of Active Protein Phosphatase-1 Inhibitor-1 Enhances Basal Cardiac Function and Protects Against Ischemia/Reperfusion Injury. Circulation Research, 104(8), 1012-1020. https://doi.org/10.1161/CIRCRESAHA.108.189811