PAI-1 Regulates the Cytoskeleton and Intrinsic Stiffness of Vascular Smooth Muscle Cells.

Autor:	Khoukaz HB; Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia., Vadali M; Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia., Schoenherr A; Medical Pharmacology and Physiology (A.S., C.A.F., S.-Y.C., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia., Ramirez-Perez FI; Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia., Morales-Quinones M; Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia., Sun Z; Dalton Cardiovascular Research Center (Z.S., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia., Fujie S; Faculty of Sport and Health Science, Ritsumeikan University, Kusatsu, Shiga, Japan (S.F.)., Foote CA; Medical Pharmacology and Physiology (A.S., C.A.F., S.-Y.C., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia., Lyu Z; Electrical Engineering and Computer Science (Z.L., S.Z.), University of Missouri, Columbia., Zeng S; Electrical Engineering and Computer Science (Z.L., S.Z.), University of Missouri, Columbia., Augenreich MA; Nutrition and Exercise Physiology (M.A.A.), University of Missouri, Columbia., Cai D; Surgery (D.C., S.-Y.C.), University of Missouri, Columbia., Chen SY; Medical Pharmacology and Physiology (A.S., C.A.F., S.-Y.C., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia.; Surgery (D.C., S.-Y.C.), University of Missouri, Columbia.; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (S.-Y.C., W.P.F.)., Joshi T; Health Management and Informatics (T.J.), University of Missouri, Columbia., Ji Y; Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia., Hill MA; Medical Pharmacology and Physiology (A.S., C.A.F., S.-Y.C., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia.; Dalton Cardiovascular Research Center (Z.S., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia., Martinez-Lemus LA; Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia.; Medical Pharmacology and Physiology (A.S., C.A.F., S.-Y.C., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia.; Dalton Cardiovascular Research Center (Z.S., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia., Fay WP; Departments of Medicine (H.B.K., M.V., F.I.R.-P., M.M.-Q., Y.J., L.A.M.-L., W.P.F.), University of Missouri, Columbia.; Medical Pharmacology and Physiology (A.S., C.A.F., S.-Y.C., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia.; Dalton Cardiovascular Research Center (Z.S., M.A.H., L.A.M.-L., W.P.F.), University of Missouri, Columbia.; Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO (S.-Y.C., W.P.F.).
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2024 Oct; Vol. 44 (10), pp. 2191-2203. Date of Electronic Publication: 2024 Jun 13.
DOI:	10.1161/ATVBAHA.124.320938
Abstrakt:	Background: Plasma concentration of PAI-1 (plasminogen activator inhibitor-1) correlates with arterial stiffness. Vascular smooth muscle cells (SMCs) express PAI-1, and the intrinsic stiffness of SMCs is a major determinant of total arterial stiffness. We hypothesized that PAI-1 promotes SMC stiffness by regulating the cytoskeleton and that pharmacological inhibition of PAI-1 decreases SMC and aortic stiffness. Methods: PAI-039, a specific inhibitor of PAI-1, and small interfering RNA were used to inhibit PAI-1 expression in cultured human SMCs. Effects of PAI-1 inhibition on SMC stiffness, F-actin (filamentous actin) content, and cytoskeleton-modulating enzymes were assessed. WT (wild-type) and PAI-1-deficient murine SMCs were used to determine PAI-039 specificity. RNA sequencing was performed to determine the effects of PAI-039 on SMC gene expression. In vivo effects of PAI-039 were assessed by aortic pulse wave velocity. Results: PAI-039 significantly reduced intrinsic stiffness of human SMCs, which was accompanied by a significant decrease in cytoplasmic F-actin content. PAI-1 gene knockdown also decreased cytoplasmic F-actin. PAI-1 inhibition significantly increased the activity of cofilin, an F-actin depolymerase, in WT murine SMCs, but not in PAI-1-deficient SMCs. RNA-sequencing analysis suggested that PAI-039 upregulates AMPK (AMP-activated protein kinase) signaling in SMCs, which was confirmed by Western blotting. Inhibition of AMPK prevented activation of cofilin by PAI-039. In mice, PAI-039 significantly decreased aortic stiffness and tunica media F-actin content without altering the elastin or collagen content. Conclusions: PAI-039 decreases intrinsic SMC stiffness and cytoplasmic stress fiber content. These effects are mediated by AMPK-dependent activation of cofilin. PAI-039 also decreases aortic stiffness in vivo. These findings suggest that PAI-1 is an important regulator of the SMC cytoskeleton and that pharmacological inhibition of PAI-1 has the potential to prevent and treat cardiovascular diseases involving arterial stiffening. Competing Interests: None.
Databáze:	MEDLINE
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