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(Circulation Research. 2009;105:249.)
© 2009 American Heart Association, Inc.

Cellular Biology

Poldip2, a Novel Regulator of Nox4 and Cytoskeletal Integrity in Vascular Smooth Muscle Cells

Alicia N. Lyle, Nita N. Deshpande, Yoshihiro Taniyama, Bonnie Seidel-Rogol, Lily Pounkova, Pingfeng Du, Christopher Papaharalambus, Bernard Lassègue, Kathy K. Griendling

From the Department of Medicine (A.N.L., N.N.D., B.S.-R., L.P., P.D., C.P., B.L., K.K.G.), Division of Cardiology, Emory University School of Medicine, Atlanta, Ga. Present address for Y.T.: Department of Vascular and Geriatric Medicine, Kinki University School of Medicine, Osaka, Japan.

Correspondence to Kathy K. Griendling, Emory University, Division of Cardiology, 319 WMB, 1639 Pierce Dr, Atlanta, GA 30322. E-mail kgriend{at}emory.edu

Rationale: NADPH oxidases (Noxes) regulate vascular physiology and contribute to the pathogenesis of vascular disease. In vascular smooth muscle cells (VSMCs), the interactions of individual Nox homologs with regulatory proteins are poorly defined.

Objective: The objective of this study was to identify novel NADPH oxidase regulatory proteins.

Methods and Results: Using a yeast 2-hybrid screen, we identified a novel p22phox binding partner, Poldip2, and demonstrated that it associates with p22phox, NADPH oxidase (Nox)1, and Nox4 and colocalizes with p22phox at sites of Nox4 localization. Poldip2 increases Nox4 enzymatic activity by 3-fold and positively regulates basal reactive oxygen species production in VSMCs (O₂^·–: 86.3±15.6% increase; H₂O₂: 40.7±4.5% increase). Overexpression of Poldip2 activates Rho (180.2±24.8% increase), strengthens focal adhesions, and increases stress fiber formation. These phenotypic changes are blocked by dominant negative Rho. In contrast, depletion of either Poldip2 or Nox4 results in a loss of these structures, which is rescued by adding back active Rho. Cell migration, which requires dynamic cytoskeletal remodeling, is impaired by either excess (70.1±14.7% decrease) or insufficient Poldip2 (63.5±5.9% decrease).

Conclusions: These results suggest that Poldip2 associates with p22phox to activate Nox4, leading to regulation of focal adhesion turnover and VSMC migration, thus linking reactive oxygen species production and cytoskeletal remodeling. Poldip2 may be a novel therapeutic target for vascular pathologies with a significant VSMC migratory component, such as restenosis and atherosclerosis.

Key Words: Nox4 • Poldip2 • vascular smooth muscle cells • reactive oxygen species • cytoskeleton

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