Grants and Contracts Details
Description
The overall goal of the application is to elucidate the signal transduction pathways that mediate Angiotensin II
(Ang II)-induced RGS2 up-regulation in vascular smooth muscle cells (RVSC). RGS2 (Regulator of G-protein
signaling-2) is a member of the GTPase activating protein family that rapidly tums off G-protein coupled
receptor signaling. A critical role of RGS2 in the regulation of blood pressure is indicated by reports that both
homozygous and heterozygous RGS2 knockout mice exhibited a severe hypertension. Further, Ang II, one of
the most important modulators in blood pressure regulation, was recently shown to dynamically stimulate
RGS2 expression in RVSC. Up-regulation of RGS2 by Ang II may be a potentially important negative feedback
mechanism that can restrain the Ang II-induced blood pressure increase, and thereby is critical in maintaining
blood pressure homeostasis under physiological condition. However, the signaling pathway that mediates Ang
II-induced RGS2 expression is mostly unknown. Our recent data suggest that a calcium independent
phospholipase A2 (iPLA2) is required for Ang II-induced RGS2 up-regulation in RVSC. We propose to test the
hypothesis that Ang II induced and PKC/PKA mediated arachidonic acid release by the nuclear iPLA2 is a
prerequisite for up-regulation of RGS2 expression by Ang II in RVSC. Specific aims are (1) To determine
whether iPLA2 is the downstream effector of PKC and PKA in Ang II-induced RGS2 up-regulation. (2) To
determine whether arachidonic acid (AA) released by iPLA2 is required for Ang II-induced RGS2 up-regulation.
(3) To determine whether the nuclear localization of iPLA2 is required for Ang II-induced and PKC/PKAmediated
RGS2 up-regulation. To achieve these aims, the cultured primary rat aorta smooth muscle cells will
be infected by the adenovirus that expresses siRNA (that targets to iPLA2), GFP, wild-type and mutant
iPLA2s. Cells will be treated with iPLA2 inhibitor (BEL) or Ang II, PMA, forskolin, arachidonic acids. The
overexpression of GFP and iPLA2 proteins will be monitored by immuno-fluorescence microscopy and
Western blot The RGS2 mRNA expression will be determined by real-time PCR. The ultimate aim of this
proposal is designed to elucidate the signaling mechanism at molecular level by which Ang II up-regulates
RGS2 in RVSC. Therefore, the new information generated by this proposed may potentially identity new
therapeutic targets for the treatment of hypertension.
Status | Finished |
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Effective start/end date | 1/1/04 → 12/31/06 |
Funding
- American Heart Association: $110,561.00
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