Drug Targeting of Plasminogen Activator Inhibitor-1 Inhibits Metabolic Dysfunction and Atherosclerosis in a Murine Model of Metabolic Syndrome

被引:46
作者
Khoukaz, Hekmat B. [1 ]
Ji, Yan [1 ]
Braet, Drew J. [1 ]
Vadali, Manisha [1 ]
Abdelhamid, Ahmed A. [1 ]
Emal, Cory D. [4 ]
Lawrence, Daniel A. [5 ]
Fay, William P. [1 ,2 ,3 ]
机构
[1] Univ Missouri, Sch Med, Dept Med, Columbia, MO 65212 USA
[2] Univ Missouri, Sch Med, Dept Med Pharmacol & Physiol, Columbia, MO 65212 USA
[3] Harry S Truman Mem Vet Hosp, Res Serv, Columbia, MO 65201 USA
[4] Eastern Michigan Univ, Dept Chem, Ypsilanti, MI 48197 USA
[5] Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI USA
基金
美国国家卫生研究院;
关键词
atherosclerosis; cellular senescence; fibrinolysis; metabolic syndrome; muscle; smooth; obesity; plasminogen activator inhibitor-1; HIGH-AFFINITY BINDING; DIET-INDUCED OBESITY; ADIPOSE-TISSUE; PHARMACOLOGICAL INHIBITION; INSULIN-RESISTANCE; PAI-1; RECEPTOR; DEFICIENCY; SENESCENCE; GROWTH;
D O I
10.1161/ATVBAHA.119.313775
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: Enhanced expression of PAI-1 (plasminogen activator inhibitor-1) has been implicated in atherosclerosis formation in humans with obesity and metabolic syndrome. However, little is known about the effects of pharmacological targeting of PAI-1 on atherogenesis. This study examined the effects of pharmacological PAI-1 inhibition on atherosclerosis formation in a murine model of obesity and metabolic syndrome. Approach and Results: LDL receptor-deficient (ldlr(-/-)) mice were fed a Western diet high in cholesterol, fat, and sucrose to induce obesity, metabolic dysfunction, and atherosclerosis. Western diet triggered significant upregulation of PAI-1 expression compared with normal diet controls. Addition of a pharmacological PAI-1 inhibitor (either PAI-039 or MDI-2268) to Western diet significantly inhibited obesity and atherosclerosis formation for up to 24 weeks without attenuating food consumption. Pharmacological PAI-1 inhibition significantly decreased macrophage accumulation and cell senescence in atherosclerotic plaques. Recombinant PAI-1 stimulated smooth muscle cell senescence, whereas a PAI-1 mutant defective in LRP1 (LDL receptor-related protein 1) binding did not. The prosenescent effect of PAI-1 was blocked by PAI-039 and R2629, a specific anti-LRP1 antibody. PAI-039 significantly decreased visceral adipose tissue inflammation, hyperglycemia, and hepatic triglyceride content without altering plasma lipid profiles. Conclusions: Pharmacological targeting of PAI-1 inhibits atherosclerosis in mice with obesity and metabolic syndrome, while inhibiting macrophage accumulation and cell senescence in atherosclerotic plaques, as well as obesity-associated metabolic dysfunction. PAI-1 induces senescence of smooth muscle cells in an LRP1-dependent manner. These results help to define the role of PAI-1 in atherosclerosis formation and suggest a new plasma-lipid-independent strategy for inhibiting atherogenesis.
引用
收藏
页码:1479 / 1490
页数:12
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