Abstract
Background: The metabolic syndrome (MetS) and aging are associated with modifications in blood coagulation factors, vascular inflammation, and increased risk of thrombosis.Objectives: Our aim was to determine concomitant changes in thrombin generation in the blood compartment and at the surface of vascular smooth muscle cells (VSMCs) and its interplay with adipokines, free fatty acids (FFA), and metalloproteinases (MMPs) in obese Zucker rats that share features of the human MetS.Methods: Obese and age-matched lean Zucker rats were compared at 25 and 80 weeks of age. Thrombin generation was assessed by calibrated automated thrombography (CAT).Results: Endogenous thrombin potential (ETP) was increased in obese rats independent of platelets and age. Clot half-lysis time was delayed with obesity and age. Interleukin (IL)-1β and IL-13 were increased with obesity and age respectively. Addition of exogenous fibrinogen, leptin, linoleic, or palmitic acid increased thrombin generation in plasma whereas adiponectin had an opposite effect. ETP was increased at the surface of VSMCs from obese rats and addition of exogenous palmitic acid further enhanced ETP values. Gelatinase activity was increased in aorta at both ages in obese rats and MMP-2 activity was increased in VSMCs from obese rats.Conclusions: Our study demonstrated in MetS an early prothrombotic phenotype of the blood compartment reinforced by procoagulant properties of dedifferentiated and inflammatory VSMCs. Mechanisms involved (1) increased fibrinogen and impaired fibrinolysis and (2) increased saturated fatty acids responsible for additive procoagulant effects. Whether specifically targeting this hypercoagulability using direct thrombin inhibitors would improve outcome in MetS is worth investigating.
Highlights
Atherothrombotic events and venous thromboembolism are associated with the metabolic syndrome (MetS), a cluster of risk factors for cardiovascular disease including insulin resistance (IR), abdominal adiposity, dyslipidemia, and hypertension (Dandona et al, 2005)
We have developed a strategy combining “adult” (25-week-old) and “old” (80-week-old) Zucker rats with MetS characteristics and their lean controls and a vascular smooth muscle cell (VSMC) approach to investigate the role of free fatty acid (FFA) and vascular inflammation in the prothrombotic properties of MetS
Platelet count in blood was increased in MSZR at both ages compared to the same aged LZR (Table 1)
Summary
Atherothrombotic events and venous thromboembolism are associated with the metabolic syndrome (MetS), a cluster of risk factors for cardiovascular disease including insulin resistance (IR), abdominal adiposity, dyslipidemia, and hypertension (Dandona et al, 2005). Inflammation in MetS results in endothelial dysfunction and increased arterial stiffness (Weiss et al, 2013), probably through the action of matrix metalloproteinases (MMPs; Halcox et al, 2009). Aging is associated with intimal thickening, breaks in the internal elastic lamina and impaired endothelial function leading to increased arterial stiffness (Wang et al, 1996). As far as fibrinolysis is concerned, chronic inflammation, abdominal obesity, and IR all increase plasminogen activator inhibitor-1 (PAI-1) production, so reducing plasminogen conversion and leading to a hypofibrinolytic state (Alessi and Juhan-Vague, 2008; Suehiro et al, 2012). The metabolic syndrome (MetS) and aging are associated with modifications in blood coagulation factors, vascular inflammation, and increased risk of thrombosis
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