title: Regulation of cardiac hypertrophic signaling by prolyl isomerase Pin1.
abstract: BACKGROUND
  Cardiac hypertrophy results from the complex interplay of differentially regulated cascades based on the phosphorylation status of involved signaling molecules. Although numerous critical regulatory kinases and phosphatases have been identified in the myocardium, the intracellular mechanism for temporal regulation of signaling duration and intensity remains obscure. In the nonmyocyte context, control of folding, activity, and stability of proteins is mediated by the prolyl isomerase Pin1, but the role of Pin1 in the heart is unknown.
  
  
  OBJECTIVE
  To establish the role of Pin1 in the heart.
  
  
  RESULTS
  Here, we show that either genetic deletion or cardiac overexpression of Pin1 blunts hypertrophic responses induced by transaortic constriction and consequent cardiac failure in vivo. Mechanistically, we find that Pin1 directly binds to Akt, mitogen activated protein kinase (MEK), and Raf-1 in cultured cardiomyocytes after hypertrophic stimulation. Furthermore, loss of Pin1 leads to diminished hypertrophic signaling of Akt and MEK, whereas overexpression of Pin1 increases Raf-1 phosphorylation on the autoinhibitory site Ser259, leading to reduced MEK activation.
  
  
  CONCLUSIONS
  Collectively, these data support a role for Pin1 as a central modulator of the intensity and duration of 2 major hypertrophic signaling pathways, thereby providing a novel target for regulation and control of cardiac hypertrophy.
authors.affiliation: Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, CA, USA.
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Toko
authors.forename: Mathias H
authors.initials: MH
authors.lastname: Konstandin
authors.forename: Shirin
authors.initials: S
authors.lastname: Doroudgar
authors.forename: Lucia
authors.initials: L
authors.lastname: Ormachea
authors.forename: Eri
authors.initials: E
authors.lastname: Joyo
authors.forename: Anya Y
authors.initials: AY
authors.lastname: Joyo
authors.forename: Shabana
authors.initials: S
authors.lastname: Din
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Gude
authors.forename: Brett
authors.initials: B
authors.lastname: Collins
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Thuerauf
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Glembotski
authors.forename: Chun-Hau
authors.initials: CH
authors.lastname: Chen
authors.forename: Kun Ping
authors.initials: KP
authors.lastname: Lu
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Müller
authors.forename: Takafumi
authors.initials: T
authors.lastname: Uchida
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sussman
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection; D014463:Ultrasonography; D048490:raf Kinases / Q000378:metabolism
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse