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Articles by Z Fan
Total Records ( 3 ) for Z Fan
  Z Fan
  Background:

Human osteoarthritic (OA) chondrocytes were previously classified into L (low)- and H (high)-OA according to matrix metalloproteinase-13 (MMP-13) basal levels and interleukin 1β (IL1β) inducibility. In H-OA chondrocytes, the regulatory proteins p130cas and nuclear matrix protein 4 (NMP4) acting on the MMP-13 promoter were identified.

Objective:

To identify regulators of MMP-13 expression/production in human L-OA chondrocytes, to determine their effect on the expression of other MMPs and the effect of IL1β on these molecules.

Methods:

The identification of the L-OA chondrocyte proteins interacting specifically with the AGRE site of the MMP-13 promoter was performed by mass spectrometry. Heat shock protein 90β (Hsp90β), p130cas and NMP4 small interfering RNAs (siRNAs) were transfected into L-OA chondrocytes and incubated with or without IL1β. Gene expression was determined by real-time PCR, MMP-1 and MMP-13 production by ELISA, and signalling pathway activation by western blotting and ELISA.

Results:

Hsp90β was identified as a protein of the L-OA/AGRE-specific complex. Silencing p130cas and Hsp90β significantly increased MMP-13 expression (about four- and twofold, respectively) and production. sip130cas affected to a lesser extent MMP-1 expression (twofold) and production. siNMP4 showed no effect. Expression of MMP-2, -3, -9 and -14 was unaffected. Silencing both Hsp90β and p130cas had a significant additive effect on MMP-13, but not on MMP-1 expression, the level of which was similar to that with sip130cas alone. IL1β decreased p130cas and Hsp90β expression/production, indicating another pathway by which this cytokine upregulates MMP expression. The IL1β-triggered signalling pathways responsible for MMP upregulation were unaffected in the silenced cells.

Conclusion:

This study illustrates the complex regulation of MMP-13 by showing the inhibitory effect of the two cytoplasmic molecules, p130cas and Hsp90β, in L-OA chondrocytes.

  M Chen , J Gu , G. L Delclos , A. M Killary , Z Fan , M. A. T Hildebrandt , R. M Chamberlain , H. B Grossman , C. P Dinney and X. Wu
 

The phosphoinositide-3 kinase (PI3K)–AKT– mammalian target of rapamycin (mTOR) pathway is an important cellular pathway controlling cell growth, tumorigenesis, cell invasion and drug response. We hypothesized that genetic variations in the PI3K–AKT–mTOR pathway may affect the survival in muscle invasive and metastatic bladder cancer (MiM-BC) patients. We conducted a follow-up study of 319 MiM-BC patients to systematically evaluate 289 single-nucleotide polymorphisms (SNPs) of 20 genes in the PI3K–AKT–mTOR pathway as predicators of survival. In multivariate Cox regression, AKT2 rs3730050, PIK3R1 rs10515074 and RAPTOR rs9906827 were significantly associated with survival. In combined analysis, we found a cumulative effect of these three SNPs on survival. With the increasing number of unfavorable genotypes, there was a significant trend of higher risk of death in multivariate Cox regression (P for trend <0.001) and shorter median survival time in Kaplan–Meier estimates (P log rank <0.001). This is the first study to evaluate the role of germ line genetic variations in the PI3K–AKT–mTOR pathway genes as predictors of MiM-BC clinical outcomes. These findings warrant further replication in independent populations and may provide information on disease management and development of target therapies.

  J Zhang , L Villacorta , L Chang , Z Fan , M Hamblin , T Zhu , C. S Chen , M. P Cole , F. J Schopfer , C. X Deng , M. T Garcia Barrio , Y. H Feng , B. A Freeman and Y. E. Chen
  Rationale:

Nitro-oleic acid (OA-NO2) is a bioactive, nitric-oxide derived fatty acid with physiologically relevant vasculoprotective properties in vivo. OA-NO2 exerts cell signaling actions as a result of its strong electrophilic nature and mediates pleiotropic cell responses in the vasculature.

Objective:

The present study sought to investigate the protective role of OA-NO2 in angiotensin (Ang) II–induced hypertension.

Methods and Results:

We show that systemic administration of OA-NO2 results in a sustained reduction of Ang II–induced hypertension in mice and exerts a significant blood pressure lowering effect on preexisting hypertension established by Ang II infusion. OA-NO2 significantly inhibits Ang II contractile response as compared to oleic acid (OA) in mesenteric vessels. The improved vasoconstriction is specific for the Ang II type 1 receptor (AT1R)-mediated signaling because vascular contraction by other G-protein–coupled receptors is not altered in response to OA-NO2 treatment. From the mechanistic viewpoint, OA-NO2 lowers Ang II–induced hypertension independently of peroxisome proliferation-activated receptor (PPAR) activation. Rather, OA-NO2, but not OA, specifically binds to the AT1R, reduces heterotrimeric G-protein coupling, and inhibits IP3 (inositol-1,4,5-trisphosphate) and calcium mobilization, without inhibiting Ang II binding to the receptor.

Conclusions:

These results demonstrate that OA-NO2 diminishes the pressor response to Ang II and inhibits AT1R-dependent vasoconstriction, revealing OA-NO2 as a novel antagonist of Ang II–induced hypertension.

 
 
 
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