title: Effects of PP1-12, a novel protein phosphatase-1 inhibitor, on ventricular function and remodeling after myocardial infarction in rats.
abstract: : PP1-12, a new protein phosphatase-1 inhibitor, is designed and synthesized to modulate the endoplasmic reticulum (ER) stress apoptotic pathway, which is involved in various cardiovascular diseases. In this study, we examined the effect of PP1-12 on ventricular remodeling and heart function after myocardial infarction. Rats that survived within 24 hours after coronary ligation were randomly divided into 6 groups and treated with normal saline, vehicle, PP1-12 at 1, 3, and 10 mg·kg·d and perindopril at 2 mg·kg·d for 4 weeks, respectively. At the end of the follow-up point, we evaluated echocardiographic and hemodynamic parameters, myocardial pathomorphology, apoptosis, and interstitial fibrosis, as well as the expression levels of important proteins involved in ER stress and apoptosis. Left ventricular geometry and function were ameliorated by PP1-12. PP1-12 inhibited interstitial fibrosis and reduced apoptosis of cardiomyocytes in a dose-dependent manner. PP1-12 decreased GRP78 and caspase-12 expression and increased p-eIF2α and Bcl-2/Bax expression. These results suggest that PP1-12 efficiently inhibits left ventricular remodeling and improves heart function. The mechanism involved may be associated with the ability of PP1-12 to depress myocardial apoptosis induced by ER stress.
authors.affiliation: *Chinese PLA General Hospital, Beijing, China; †School of Medicine, Nankai University, Tianjin, China; and ‡Beijing Institute of Pharmacology and Toxicology, Beijing, China.
authors.forename: Yun-Yun
authors.initials: YY
authors.lastname: He
authors.forename: Chun-Lei
authors.initials: CL
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Wu
authors.initials: W
authors.lastname: Zhong
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.forename: Kun-Lun
authors.initials: KL
authors.lastname: He
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Wang
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006352:Heart Ventricles / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors*; D017207:Rats, Sprague-Dawley; D013890:Thiourea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: C000598524:3-(thiophen-2-yl)-N-(2,2,2-trichloro-1-(3-(2-methoxyphenyl)thioureido)ethyl)acrylamide; D000178:Acrylamides; D004791:Enzyme Inhibitors; D054645:Protein Phosphatase 1; D013890:Thiourea