PAI-1 Levels are Related to Insulin Resistance and Carotid Atherosclerosis in Subjects with Familial Combined Hyperlipidemia

Abstract

Familial combined hyperlipidemia (FCH) is a primary atherogenic dyslipidemia with insulin resistance and increased cardiovascular risk. Plasminogen activator inhibitor type 1 (PAI-1) and myeloperoxidase (MPO) activity are associated with proinflammatory and atherothrombotic risk. Our aim was to study the role played by PAI-1 and MPO activity in the carotid atherosclerosis prevalence in FCH subjects. 36 FCH unrelated subjects (17 women) were matched by age and body weight with 36 healthy normolipidemic subjects (19 female). Blood lipids, glucose, insulin, insulin resistance (homeostasis model assessment (HOMA)), MPO, and PAI-1 were determined in both groups. Carotid intima media thickness (IMT) was measured by the same investigator by standardized protocol. No differences in age, body mass index (BMI) or waist circumference were observed between the two groups. HOMA and PAI-1 values were higher in the FCH group, reaching statistical significance in those subjects with insulin resistance. In addition, PAI-1 values correlated significantly with metabolic syndrome components and carotid IMT. It is known that the elevated cardiovascular risk that characterizes FCH is frequently associated with insulin resistance. We have detected that two known proinflammatory and proatherothrombotic factors (MPO and PAI-1) are significantly elevated in FCH subjects with insulin resistance. These results could partly explain the high cardiovascular risk present in FCH subjects.

A Narrative Review on Plasminogen Activator Inhibitor-1 and Its (Patho)Physiological Role: To Target or Not to Target?

“…Furthermore, studies on the effects of pharmacological PAI-1 inhibition on atherogenesis in mice with obesity and metabolic syndrome also suggested a role for PAI-1 in adipose tissue inflammation, macrophage accumulation, and inducing senescence of smooth muscle cells through its interaction with LRP1 [ 49 ]. Whereas several studies demonstrated substantial evidence for PAI-1 as an independent risk factor for CVD including myocardial infarction and stroke [ 50 , 51 , 52 ], coronary heart disease [ 53 ], venous thrombosis [ 54 ], and atherosclerosis [ 45 , 55 ], other studies could not confirm these associations or the significance for the link was lost after adjusting for other risk factors, such as age, sex, and metabolic abnormities [ 52 , 56 , 57 , 58 ].…”

Metabolic Syndrome Pathophysiology and Predisposing Factors

“…The PAI-1 is a highly responsive/induced adipokine by pro-inflammatory cytokines and ROS, especially cytokines related to VAT and hepatic ectopic fat such as TNF-α, transforming growth factorbeta (TGF-β) and insulin [82]. Strongly connected to MetS pathophysiology, it has become an important biomarker to evaluate the syndrome severity due to its association with IR, non-alcoholic fatty liver disease, a proinflammatory and prothrombotic state [83,84]. The major pathogenic contribution of PAI-1 to the MetS' risk factors cluster is linked to the establishment of a prothrombotic state as found in patients with elevated circulating levels of this cytokine.…”

Fibrinolytic Markers Could Be Useful Predictors of Severity in Patients With Pulmonary Arterial Hypertension: a Retrospective Study

“…It complements the activities of protein anticoagulants and endothelial-derived platelet inhibitors, such as proteins C, S, anti-thrombin III, and nitric oxide [5]. It is an endogenous defense mechanism for the prevention of atherosclerotic change, and there are some reports that the tPAI-1 levels are positively and independently associated with the degree of IMT [6,7].…”

“…tPAI-1 is known to be associated with a proin ammatory atherosclerotic risk. Moreover, there are reports that tPAI-1 is independently associated with the degree of intima media thickness (IMT) [6,7]. Thrombomodulin (TM) has an anticoagulant effect that is stimulated by activating protein C, and this is corroborated by reports about elevated blood levels of TM in patients with acute pulmonary embolism [8,9].…”