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Pharmacological Targeting of Plasminogen Activator Inhibitor-1 Decreases Vascular Smooth Muscle Cell Migration and Neointima Formation.

ABSTRACT: Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor that promotes and inhibits cell migration, plays a complex and important role in adverse vascular remodeling. Little is known about the effects of pharmacological PAI-1 inhibitors, an emerging drug class, on migration of vascular smooth muscle cells (SMCs) and endothelial cells (ECs), crucial mediators of vascular remodeling. We investigated the effects of PAI-039 (tiplaxtinin), a specific PAI-1 inhibitor, on SMC and EC migration in vitro and vascular remodeling in vivo.PAI-039 inhibited SMC migration through collagen gels, including those supplemented with vitronectin and other extracellular matrix proteins, but did not inhibit migration of PAI-1-deficient SMCs, suggesting that its antimigratory effects were PAI-1-specific and physiologically relevant. However, PAI-039 did not inhibit EC migration. PAI-039 inhibited phosphorylation and nuclear translocation of signal transducers and activators of transcription-1 in SMCs, but had no discernable effect on signal transducer and activator of transcription-1 signaling in ECs. Expression of low-density lipoprotein receptor-related protein 1, a motogenic PAI-1 receptor that activates Janus kinase/signal transducers and activators of transcription-1 signaling, was markedly lower in ECs than in SMCs. Notably, PAI-039 significantly inhibited intimal hyperplasia and inflammation in murine models of adverse vascular remodeling, but did not adversely affect re-endothelialization after endothelium-denuding mechanical vascular injury.PAI-039 inhibits SMC migration and intimal hyperplasia, while having no inhibitory effect on ECs, which seems to be because of differences in PAI-1-dependent low-density lipoprotein receptor-related protein 1/Janus kinase/signal transducer and activator of transcription-1 signaling between SMCs and ECs. These findings suggest that PAI-1 may be an important therapeutic target in obstructive vascular diseases characterized by neointimal hyperplasia.

SUBMITTER: Ji Y

PROVIDER: S-EPMC5102271 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Pharmacological Targeting of Plasminogen Activator Inhibitor-1 Decreases Vascular Smooth Muscle Cell Migration and Neointima Formation.

Ji Yan Y Weng Zhen Z Fish Philip P Goyal Neha N Luo Mao M Myears Samantha P SP Strawn Tammy L TL Chandrasekar Bysani B Wu Jianbo J Fay William P WP

Arteriosclerosis, thrombosis, and vascular biology 20160922 11

<h4>Objective</h4>Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor that promotes and inhibits cell migration, plays a complex and important role in adverse vascular remodeling. Little is known about the effects of pharmacological PAI-1 inhibitors, an emerging drug class, on migration of vascular smooth muscle cells (SMCs) and endothelial cells (ECs), crucial mediators of vascular remodeling. We investigated the effects of PAI-039 (tiplaxtinin), a specific PAI-1 inhibitor, o ...[more]

PMID: 27659097

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Project description:SMCs express plasminogen activator inhibitor-1 (PAI-1), which regulates SMC function and vascular remodeling. However, whether PAI-1 controls SMC cytoskeletal dynamics and stiffness is unknown, and the causal role of PAI-1 in arterial stiffening is undefined. SMCs from human coronary arteries and aortae of wild-type vs. PAI-1-deficient mice were cultured with or without PAI-039, a specific PAI-1 inhibitor, after which cell stiffness was measured by atomic force microscopy, filamentous actin structures were assessed by confocal microscopy, and the activities cofilin, LIM domain kinase 1 (LIMK), slingshot homolog 1 (SSH), and AMP-activated protein kinase (AMPK) were measured. RNA sequencing was performed to determine the effects of PAI-039 on SMC gene expression. Effects of PAI-039 on aortic stiffness were assessed by pulse wave velocity. PAI-039 significantly reduced intrinsic stiffness of human SMCs, which was accompanied by significant decreases in cytoplasmic actin filaments. Similar effects were observed in wild-type, but not in PAI-1-deficient SMCs. Mechanistically, PAI-039 significantly increased the activity of cofilin, an actin depolymerase, in SMCs expressing PAI-1, but not in PAI-1-deficient cells. PAI-039 had no significant effects on LIMK or SSH activity. RNA-sequencing analysis suggested that PAI-039 up-regulates AMPK 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 without significantly altering peri-aortic fibrosis. PAI-039 decreases intrinsic SMC stiffness by reducing 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 pharmacologic inhibition of PAI-1 has potential to treat cardiovascular diseases mediated by accelerated arterial stiffening.

Dataset Information

Pharmacological Targeting of Plasminogen Activator Inhibitor-1 Decreases Vascular Smooth Muscle Cell Migration and Neointima Formation.

Publications

Pharmacological Targeting of Plasminogen Activator Inhibitor-1 Decreases Vascular Smooth Muscle Cell Migration and Neointima Formation.

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