Inhibition of farnesyl pyrophosphate synthase prevents norepinephrine-induced fibrotic responses in vascular smooth muscle cells from spontaneously hypertensive rats.

Abstract

Both norepinephrine (NE) and connective tissue growth factor (CTGF) contribute to vascular fibrosis during hypertension. Recent studies indicate that farnesyl pyrophosphate synthase (FPPS) plays an important role in cardiac remodeling in hypertension. However, the role of FPPS in NE-induced fibrotic responses and related molecular mechanisms is unknown. Vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were stimulated with NE. The fibrotic responses were assessed by measuring CTGF, hydroxyproline (hyp), and α-1 procollagen I levels using Western blot, a hydroxyproline test kit, and real-time quantitative PCR assays, respectively. Ras activity was determined by a pull-down assay using a Ras activation assay kit and detected by Western blot. NE dose-dependently increased fibrosis in SHR-VSMCs, and this increase was significantly reduced by ibandronate, an inhibitor of FPPS. The addition of farnesol, but not geranylgeraniol, partially reversed the inhibitory effects of ibandronate. Furthermore, the anti-fibrotic effects of ibandronate could be mimicked by FTI-276 but not by GGTI-286. A pull-down assay showed that ibandronate reduced the NE-induced Ras activation. Moreover, ibandronate inhibited the NE-induced activation of p38, JNK, and ERK1/2. Only SB203580 (specific inhibitor of p38) diminished the NE-induced CTGF production. These results demonstrated that inhibiting FPPS prevents NE-induced fibrotic responses in SHR-VSMCs and that the Ras kinase and p38 pathways were the underlying mechanisms involved in this process.

• Authors: Chang-Qing Du, Lin Yang, Jian Yang, Jie Han, Xiao-Sheng Hu, Tao Wu, Shen-Jiang Hu
• Journal: Hypertension research : official journal of the Japanese Society of Hypertension (Hypertens Res) Vol. 37 Issue 1 Pg. 26-34 (Jan 2014) ISSN: 1348-4214 [Electronic] England
• PMID: 23985701 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Protein Precursor
• CTFgamma protein, rat
• Diphosphonates
• Enzyme Inhibitors
• Peptide Fragments
• Polyisoprenyl Phosphates
• Sesquiterpenes
• geranyl pyrophosphate
• farnesyl pyrophosphate
• Dimethylallyltranstransferase
• Mitogen-Activated Protein Kinases
• Hydroxyproline
• Ibandronic Acid
• Norepinephrine

Topics

• Amyloid beta-Protein Precursor (metabolism)
• Animals
• Cell Proliferation (drug effects)
• Cells, Cultured
• Dimethylallyltranstransferase (antagonists & inhibitors)
• Diphosphonates (pharmacology)
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Fibrosis
• Genes, ras (physiology)
• Hydroxyproline (metabolism)
• Hypertension (drug therapy, pathology)
• Ibandronic Acid
• Mitogen-Activated Protein Kinases (metabolism)
• Muscle, Smooth, Vascular (cytology, drug effects, pathology)
• Myocytes, Smooth Muscle (drug effects, pathology)
• Norepinephrine (antagonists & inhibitors, toxicity)
• Peptide Fragments (metabolism)
• Polyisoprenyl Phosphates (metabolism)
• Rats
• Rats, Inbred SHR
• Rats, Inbred WKY
• Sesquiterpenes (metabolism)