title: Pharmacological inhibition of βIIPKC is cardioprotective in late-stage hypertrophy.
abstract: We previously found that in the hearts of hypertensive Dahl salt-sensitive rats, βIIPKC levels increase during the transition from compensated cardiac hypertrophy to cardiac dysfunction. Here we showed that a six-week treatment of these hypertensive rats with a βIIPKC-specific inhibitor, βIIV5-3, prolonged their survival by at least 6weeks, suppressed myocardial fibrosis and inflammation, and delayed the transition from compensated hypertrophy to cardiac dysfunction. In addition, changes in the levels of the Ca(2+)-handling proteins, SERCA2 and the Na(+)/Ca(2+) exchanger, as well as troponin I phosphorylation, seen in the control-treated hypertensive rats were not observed in the βΙΙPKC-treated rats, suggesting that βΙΙPKC contributes to the regulation of calcium levels in the myocardium. In contrast, treatment with the selective inhibitor of βIPKC, an alternative spliced form of βIIPKC, had no beneficial effects in these rats. We also found that βIIV5-3, but not βIV5-3, improved calcium handling in isolated rat cardiomyocytes and enhanced contractility in isolated rat hearts. In conclusion, our data using an in vivo model of cardiac dysfunction (late-phase hypertrophy), suggest that βIIPKC contributes to the pathology associated with heart failure and thus an inhibitor of βIIPKC may be a potential treatment for this disease.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305-5174, USA.
authors.forename: Julio C B
authors.initials: JC
authors.lastname: Ferreira
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Koyanagi
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Palaniyandi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fajardo
authors.forename: Eric N
authors.initials: EN
authors.lastname: Churchill
authors.forename: Grant
authors.initials: G
authors.lastname: Budas
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Disatnik
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Brum
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology* / Q000401:mortality / Q000517:prevention & control*; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005355:Fibrosis; D006333:Heart Failure / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D020303:Rats, Inbred Dahl; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism
chemical_list: D010455:Peptides; D047428:Protein Kinase Inhibitors; D019831:Sodium-Calcium Exchanger; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium