Knockdown of farnesylpyrophosphate synthase prevents angiotensin II-mediated cardiac hypertrophy

Int J Biochem Cell Biol. 2010 Dec;42(12):2056-64. doi: 10.1016/j.biocel.2010.09.010. Epub 2010 Sep 25.

Abstract

The Rho guanosine triphosphatases (Rho GTPases) family, including RhoA, plays an important role in angiotensin II (Ang II)-mediated cardiac hypertrophy. Farnesylpyrophosphate synthase (FPPS)-catalyzed isoprenoid intermediates are vital for activation of RhoA. The present study was designed to investigate the role of FPPS in myocardial hypertrophy mediated with Ang II. First, we demonstrated that FPPS expression was elevated both in cultured neonatal cardiomyocytes (NCMs) following Ang II treatment and in the hypertrophic myocardium of 18-week-old spontaneously hypertensive rats (SHRs). Then, the importance of FPPS was assessed by RNA interference (RNAi) against FPPS in NCMs. Successful FPPS silencing in NCMs completely inhibited the hypertrophy marker genes of β-myosin heavy chain (β-MHC) and brain natriuretic peptide (BNP), as well as cell surface area. Furthermore, FPPS knockdown prevented elevated RhoA activity compared with non-silenced controls. Similarly, increased-phosphorylation of p-38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPK) by Ang II was attenuated. In vivo gene transfer also attenuated hypertrophic responses as indexed by left ventricular weight/body weight (LVW/BW), heart weight/body weight (HW/BW), and echocardiography, as well as expression of β-MHC and BNP mRNA in SHRs. In conclusion, FPPS with RhoA associated p-38 and JNK MAPK signaling might play an important role in Ang II-induced cardiac hypertrophy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology*
  • Animals
  • Cardiomegaly / enzymology*
  • Cardiomegaly / metabolism
  • Dimethylallyltranstransferase / deficiency*
  • Dimethylallyltranstransferase / genetics
  • Dimethylallyltranstransferase / metabolism
  • Gene Knockdown Techniques
  • Humans
  • MAP Kinase Kinase 4 / metabolism
  • Male
  • Mitogen-Activated Protein Kinases / metabolism*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology
  • Phosphorylation
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY
  • Signal Transduction
  • Transfection
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • rhoA GTP-Binding Protein / metabolism

Substances

  • RNA, Small Interfering
  • Angiotensin II
  • Dimethylallyltranstransferase
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • rhoA GTP-Binding Protein