Abstract
Gqα signaling has been implicated in cardiac hypertrophy. In addition, angiotensin II (Ang II) was also shown to induce its hypertrophic effect through Gqα and PKCδ activation. We recently showed the role of enhanced expression of Gqα/PLCβ1 proteins in vascular smooth muscle cell (VSMC) hypertrophy, however, the role of PKCδ in VSMC hypertrophy in animal model is still lacking. The present study was therefore undertaken to examine the role of PKCδ and the associated signaling mechanisms in VSMC hypertrophy using 16-week-old spontaneously hypertensive rats (SHR). VSMC from 16-week-old SHR exhibited enhanced phosphorylation of PKCδ-Tyr311 and increased protein synthesis, marker of hypertrophy, as compared to WKY rats which was attenuated by rottlerin, an inhibitor of PKCδ. In addition, knocking down of PKCδ by PKCδ-siRNA also attenuated enhanced protein synthesis in VSMC from SHR. Furthermore, rottlerin attenuated the increased production of superoxide anion, NAD(P)H oxidase activity, increased expression of Gqα, phospholipase C (PLC)β1, insulin like growth factor-1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) proteins in VSMC from SHR. In addition, the enhanced phosphorylation of c-Src, PKCδ-Tyr311, IGF-1R, EGFR and ERK1/2 exhibited by VSMC from SHR was also attenuated by rottlerin. These results suggest that VSMC from SHR exhibit enhanced activity of PKCδ and that PKCδ is the upstream molecule of reactive oxygen species (ROS) and contributes to the enhanced expression of Gqα and PLCβ1 proteins and resultant VSMC hypertrophy involving c-Src, growth factor receptor transactivation and MAP kinase signaling.
Highlights
Essential hypertension is associated with vascular remodeling characterized by enhanced media to lumen ratio in arteries [1] and is due to increased vascular smooth muscle cell (VSMC) proliferation and hypertrophy
Since VSMC from spontaneously hypertensive rats (SHR) exhibit enhanced levels of endogenous angiotensin II (Ang II) [11] and enhanced protein synthesis [2], it was desirable to investigate if VSMC hypertrophy in SHR is attributed to the overexpression of PKCδ phosphorylated at Tyr311
We earlier showed the role of endogenous Ang II and ET-1 in the enhanced expression of Gqα and PLCβ1 proteins and the enhanced protein synthesis in VSMC from SHR through MAPKs singling [2]
Summary
Essential hypertension is associated with vascular remodeling characterized by enhanced media to lumen ratio in arteries [1] and is due to increased vascular smooth muscle cell (VSMC) proliferation and hypertrophy. The role of PKC isoforms in vascular hypertrophy is still insufficiently characterized and may vary according to cell type [17,18] These intracellular serine/threonine kinases are rapidly activated and are implicated in the regulation of cell proliferation [19] and growth [20] and likely play an important role in mediating vascular remodeling. We recently demonstrated the role of endogenous Ang II and ET-1 in enhanced expression of Gqα and PLCβ1 proteins and VSMC hypertrophy in spontaneously hypertensive rats through the activation of MAPK signaling [2]. We showed that enhanced oxidative stress exhibited by VSMC from SHR through c-Src and growth factor receptor activation increases MAP kinase signaling and enhances the expression of Gqα and PLCβ1 proteins and results in VSMC hypertrophy [29]. The present study is undertaken to examine if VSMC from SHR exhibit enhanced activation of PKCδ and its implication in VSMC hypertrophy and to further explore the signaling mechanism responsible for this process
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