Polymerase Delta Interacting Protein 2 Sustains Vascular Structure and Function

Abstract

Objective Based on previous evidence that polymerase delta interacting protein 2 (Poldip2) increases NADPH oxidase 4 (Nox4) activity in vascular smooth muscle cells (VSMC), we hypothesized that in vivo knockdown of Poldip2 would inhibit reactive oxygen species (ROS) production and alter vascular function. Approach and Results Because homozygous Poldip2 deletion is lethal, Poldip2+/− mice were employed. Poldip2 mRNA and protein levels were reduced by about 50% in Poldip2+/− aorta, with no change in p22phox, Nox1, Nox2 and Nox4 mRNAs. NADPH oxidase activity was also inhibited in Poldip2+/− tissue. Isolated aortas from Poldip2+/− mice demonstrated impaired phenylephrine and potassium chloride-induced contractions, increased stiffness and reduced compliance, associated with disruption of elastic lamellae and excessive extracellular matrix deposition. Collagen I secretion was elevated in cultured VSMC from Poldip2+/− mice and restored by H2O2 supplementation, suggesting that this novel function of Poldip2 is mediated by reactive oxygen species. Furthermore, Poldip2+/− mice were protected against aortic dilatation in a model of experimental aneurysm, an effect consistent with increased collagen secretion. Conclusions Poldip2 knockdown reduces H2O2 production in vivo, leading to increases in extracellular matrix, greater vascular stiffness and impaired agonist-mediated contraction. Thus, unaltered expression of Poldip2 is necessary for vascular integrity and function.

The diabetic proximal tubule: part of the problem, and part of the solution?

“…Although positive findings have been reported among older infants (57), the usefulness of urinary NGAL as a marker of AKI in preterm neonates remains unclear (20,23,33,34). Certainly, consistent with previous studies (20,23) we found a significant inverse correlation between urinary NGAL and gestational age at birth; these findings may relate to the immaturity of the kidney, and the clinical instability of the younger neonates.…”

“…Nox4 does not require the classical cytoplasmic subunits or Rac1, and activation of Nox4 is undisturbed in cells where Rac1 is knocked down, supporting the notion that Nox4 is Rac independent (41) and suggesting a role for other G protein transduction pathways, perhaps through RhoA. In addition, polymerase (DNA-directed) ␦-interacting protein 2 (Poldip2), a Nox4 enhancing protein, induces cytoskeletal changes, including strengthening of focal adhesions and stress fiber formation in vascular smooth muscle cells, suggesting interplay among these signaling proteins (39,57). A role for RhoA and Poldip2 interactions with Nox4 has not been explored in TGF-␤ 1 -induced myofibroblast activation.…”

PDIP38 is translocated to the spliceosomes/nuclear speckles in response to UV-induced DNA damage and is required for UV-induced alternative splicing of MDM2

“…The PDIP38 homozygous state was embryonically lethal, and the heterozygous mice exhibited defects in vascular functions. 24 In correspondence with these findings, the roles of PDIP38 are likely to be complex, and this multifunctional protein appears to participate in multiple and diverse cellular functions.…”

“…23,24,58 PDIP38 interacts with p22phox and activates Nox4 and positively regulates reactive oxygen species in vascular smooth muscle cells. These events impact focal adhesion, cytoskeletal remodeling and vascular smooth muscle migration.…”

Vascular Function

“…Turlo et al 17 showed an essential function of β1-integrin in the maintenance of vasomotor control and highlighted a critical role for β1-integrin in VSMC survival. Furthermore, Sutliff et al 18 demonstrated that Poldip2 knockdown reduces H 2 O 2 production in vivo, leading to increases in extracellular matrix, greater vascular stiffness, and impaired agonist-mediated contraction. Abnormal proliferation and migration of VSMCs are critical events in the progression of several vascular diseases, where AMP-activated protein kinase plays a crucial role in cellular proliferation and migration.…”