RATIONALE: Protein kinase Cα (PKCα) activity and protein level are induced during cardiac disease where it controls myocardial contractility and propensity to heart failure in mice and rats. For example, mice lacking the gene for PKCα have enhanced cardiac contractility and reduced susceptibility to heart failure after long-term pressure overload or after myocardial infarction injury. Pharmacological inhibition of PKCα/β with Ro-32-0432, Ro-31-8220 or ruboxistaurin (LY333531) similarly enhances cardiac function and antagonizes heart failure in multiple models of disease in both mice and rats. OBJECTIVE: Large and small mammals differ in several key indexes of heart function and biochemistry, lending uncertainty as to how PKCα/β inhibition might affect or protect a large animal model of heart failure. METHODS AND RESULTS: We demonstrate that ruboxistaurin administration to a pig model of myocardial infarction-induced heart failure was protective. Twenty-kilogram pigs underwent left anterior descending artery occlusion resulting in myocardial infarctions and were then divided into vehicle or ruboxistaurin feed groups, after which they were monitored monthly for the next 3 months. Ruboxistaurin administered pigs showed significantly better recovery of myocardial contractility 3 months after infarction injury, greater ejection fraction, and greater cardiac output compared with vehicle-treated pigs. CONCLUSIONS: These results provide additional evidence in a large animal model of disease that PKCα/β inhibition (with ruboxistaurin) represents a tenable and novel therapeutic approach for treating human heart failure.
RATIONALE: Protein kinase Cα (PKCα) activity and protein level are induced during cardiac disease where it controls myocardial contractility and propensity to heart failure in mice and rats. For example, mice lacking the gene for PKCα have enhanced cardiac contractility and reduced susceptibility to heart failure after long-term pressure overload or after myocardial infarction injury. Pharmacological inhibition of PKCα/β with Ro-32-0432, Ro-31-8220 or ruboxistaurin (LY333531) similarly enhances cardiac function and antagonizes heart failure in multiple models of disease in both mice and rats. OBJECTIVE: Large and small mammals differ in several key indexes of heart function and biochemistry, lending uncertainty as to how PKCα/β inhibition might affect or protect a large animal model of heart failure. METHODS AND RESULTS: We demonstrate that ruboxistaurin administration to a pig model of myocardial infarction-induced heart failure was protective. Twenty-kilogram pigs underwent left anterior descending artery occlusion resulting in myocardial infarctions and were then divided into vehicle or ruboxistaurin feed groups, after which they were monitored monthly for the next 3 months. Ruboxistaurin administered pigs showed significantly better recovery of myocardial contractility 3 months after infarction injury, greater ejection fraction, and greater cardiac output compared with vehicle-treated pigs. CONCLUSIONS: These results provide additional evidence in a large animal model of disease that PKCα/β inhibition (with ruboxistaurin) represents a tenable and novel therapeutic approach for treating human heart failure.
Authors: J M Pass; J Gao; W K Jones; W B Wead; X Wu; J Zhang; C P Baines; R Bolli; Y T Zheng; I G Joshua; P Ping Journal: Am J Physiol Heart Circ Physiol Date: 2001-12 Impact factor: 4.733
Authors: Guey-Shin Wang; Muge N Kuyumcu-Martinez; Satyam Sarma; Nitin Mathur; Xander H T Wehrens; Thomas A Cooper Journal: J Clin Invest Date: 2009-11-09 Impact factor: 14.808
Authors: Harvey S Hahn; Yehia Marreez; Amy Odley; Amber Sterbling; Martin G Yussman; K Chad Hilty; Ilona Bodi; Stephen B Liggett; Arnold Schwartz; Gerald W Dorn Journal: Circ Res Date: 2003-11-06 Impact factor: 17.367
Authors: N Bowling; R A Walsh; G Song; T Estridge; G E Sandusky; R L Fouts; K Mintze; T Pickard; R Roden; M R Bristow; H N Sabbah; J L Mizrahi; G Gromo; G L King; C J Vlahos Journal: Circulation Date: 1999-01-26 Impact factor: 29.690
Authors: Qinghang Liu; Xiongwen Chen; Scott M Macdonnell; Evangelia G Kranias; John N Lorenz; Michael Leitges; Steven R Houser; Jeffery D Molkentin Journal: Circ Res Date: 2009-06-25 Impact factor: 17.367
Authors: Michael Hambleton; Allen York; Michelle A Sargent; Robert A Kaiser; John N Lorenz; Jeffrey Robbins; Jeffery D Molkentin Journal: Am J Physiol Heart Circ Physiol Date: 2007-10-05 Impact factor: 4.733
Authors: Brandon P Lucke-Wold; Ryan C Turner; Aric F Logsdon; James W Simpkins; Daniel L Alkon; Kelly E Smith; Yi-Wen Chen; Zhenjun Tan; Jason D Huber; Charles L Rosen Journal: J Alzheimers Dis Date: 2015 Impact factor: 4.472
Authors: Jasmine A Luzum; Christopher Ting; Edward L Peterson; Hongsheng Gui; Tyler Shugg; L Keoki Williams; Liang Li; Wolfgang Sadee; Danxin Wang; David E Lanfear Journal: Cardiovasc Drugs Ther Date: 2019-12 Impact factor: 3.727
Authors: Ray Hu; Michael P Morley; Jeffrey Brandimarto; Nathan R Tucker; Victoria A Parsons; Sihai D Zhao; Benjamin Meder; Hugo A Katus; Frank Rühle; Monika Stoll; Eric Villard; François Cambien; Honghuang Lin; Nicholas L Smith; Janine F Felix; Ramachandran S Vasan; Pim van der Harst; Christopher Newton-Cheh; Jin Li; Cecilia E Kim; Hakon Hakonarson; Sridhar Hannenhalli; Euan A Ashley; Christine S Moravec; W H Wilson Tang; Marjorie Maillet; Jeffery D Molkentin; Patrick T Ellinor; Kenneth B Margulies; Thomas P Cappola Journal: Circ Genom Precis Med Date: 2018-03
Authors: Hyosook Hwang; Dustin Robinson; Julie B Rogers; Tamara K Stevenson; Sarah E Lang; Sakthivel Sadayappan; Sharlene M Day; Sivaraj Sivaramakrishnan; Margaret V Westfall Journal: Sci Rep Date: 2013 Impact factor: 4.379