Inducible expression of active protein phosphatase-1 inhibitor-1 enhances basal cardiac function and protects against ischemia/reperfusion injury.
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 Ca(2+) homeostasis. Because enhanced inhibitor-1 (I-1) activity has been suggested to preserve Ca(2+) 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 Ca(2+)-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.
Nicolaou
Persoulla
P
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0575, USA.
Rodriguez
Patricia
P
Ren
Xiaoping
X
Zhou
Xiaoyang
X
Qian
Jiang
J
Sadayappan
Sakthivel
S
Mitton
Bryan
B
Pathak
Anand
A
Robbins
Jeffrey
J
Hajjar
Roger J
RJ
Jones
Keith
K
Kranias
Evangelia G
EG
D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009336:Necrosis; D010766:Phosphorylation; D040901:Proteomics; D020127:Recovery of Function; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013312:Stress, Physiological; D013997:Time Factors; D015854:Up-Regulation; D016277:Ventricular Function, Left; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000099211:Phospholamban; C021042:protein phosphatase inhibitor-1