Objectives: Polymerase delta interacting protein 2 (Poldip2) has previously been implicated in migration, proliferation and extracellular matrix (ECM) production in vascular smooth muscle cells. Thereby, regulation of Poldip2 protein expression is suggested to prevent the development and progression of diabetic macroangiopathy. We recently reported that Poldip2+/- mouse aortic smooth muscle cells (MASMs) exhibit higher β1-Integrin expression and activity of the PI3K/Akt/mTOR signaling pathway, leading to increased ECM protein synthesis. We further investigated the mechanism of Podlip2 in regulating the β1-Integrin expression.

Approach and Results: Cell adhesion and cell signaling, below the focal adhesion, were investigated. Poldip2+/- MASMs (HET) showed both quicker cell attachment and detachment than Poldip2+/+ MASMs (WT). Paxillin, one of the components of focal adhesion, is expressed in all areas (from front to back) of lamellipodia in WT, on the other hand HET express the Paxillin only front area, which may induce weaker cell adhesion. The mature focal adhesion marker, Zyxin, expression is decreased in HET significantly. Intriguingly, the activity of RhoA is increased in HET and induced MRTF-A translocation from cytosol to nacreous.

Conclusions: It is revealed that Poldip2 is positive regulator of Zyxin. HET has weak cell adhesion, and may induce Poldip2+/- MASMs exhibit higher β1-Integrin expression as a compensation against immature focal adhesion. Thus PI3K/Akt/mTOR signaling pathway is activated, leading to increased ECM protein synthesis. Translocation of MRTF-A from cytosol to the nucleus, may contribute to bind to transcriptional factor for Collagen I. This phenomenon is suggested as one more pathway, which Collagen I accumulates in HET. These findings have important implications for atherosclerotic vascular diseases such as diabetic macroangiopathy in which ECM accumulation plays a role.

Disclosure

M. Fujii: None. N. Sonoda: None. M. Okamoto: None. H. Morinaga: None. Y. Ogawa: Research Support; Self; AstraZeneca. Advisory Panel; Self; Gilead Sciences, Inc.. Research Support; Self; Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.. K. Griendling: None.

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