Polymerase Delta Interacting Protein 2 Sustains Vascular Structure and Function

被引:54
作者
Sutliff, Roy L. [1 ,2 ]
Hilenski, Lula L. [3 ]
Amanso, Angelica M. [3 ]
Parastatidis, Ioannis [3 ]
Dikalova, Anna E. [3 ]
Hansen, Laura [4 ,5 ]
Datla, Srinivasa Raju [3 ]
Long, James S. [3 ]
El-Ali, Alexander M. [1 ,2 ]
Joseph, Giji [3 ]
Gleason, Rudolph L., Jr. [4 ,5 ]
Taylor, W. Robert [3 ,4 ,5 ]
Hart, C. Michael [1 ,2 ]
Griendling, Kathy K. [3 ]
Lassegue, Bernard [3 ]
机构
[1] Atlanta Vet Affairs Med Ctr, Div Pulm & Crit Care Med, Dept Med, Decatur, GA USA
[2] Emory Univ, Sch Med, Decatur, GA 30033 USA
[3] Emory Univ, Sch Med, Dept Med, Div Cardiol, Atlanta, GA 30322 USA
[4] Emory Univ, Sch Med, Wallace H Coulter Dept Biomed Engn, Atlanta, GA 30322 USA
[5] Georgia Inst Technol, Atlanta, GA 30332 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
blood vessel; extracellular matrix; hydrogen peroxide; Nox4; Poldip2; AORTIC-ANEURYSM FORMATION; SMOOTH-MUSCLE-CELLS; ALL-CAUSE MORTALITY; CARDIOVASCULAR EVENTS; EXTRACELLULAR-MATRIX; ARTERIAL STIFFNESS; HYDROGEN-PEROXIDE; COLLAGEN SECRETION; OXIDATIVE STRESS; MECHANICS;
D O I
10.1161/ATVBAHA.113.301913
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective-On the basis of previous evidence that polymerase delta interacting protein 2 (Poldip2) increases reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4) activity in vascular smooth muscle cells, we hypothesized that in vivo knockdown of Poldip2 would inhibit reactive oxygen species production and alter vascular function. Approach and Results-Because homozygous Poldip2 deletion is lethal, Poldip2(+/-) mice were used. Poldip2 mRNA and protein levels were reduced by approximate to 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 vascular smooth muscle cells 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.
引用
收藏
页码:2154 / 2161
页数:8
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