Anti-Inflammatory Effects of Simvastatin during the Resolution Phase of Experimentally Formed Venous Thrombi

Abstract

Deep venous thrombosis (DVT) is a common vascular disease and is closely linked to inflammation. Over the past decade, the potential antithrombotic effect of statins has been elucidated by clinical studies, primarily through focusing on DVT prevention. The effects of statins on DVT resolution and its underlying mechanisms have been rarely addressed. We established a rabbit model of the (IVC) venous thrombosis. After 48 hours, the rabbits were treated with saline, heparin, simvastatin, or simvastatin combined with heparin, respectively, for 14 days. The migration of inflammatory cells (neutrophils, monocytes, lymphocytes) in the thrombi and injured venous wall, the plasma levels of interleukin (IL)-6, monocyte chemotactic protein 1 (MCP-1) and P-selectin, and local expression of MCP-1 and P-selectin in the venous wall were evaluated by histology, immunohistochemistry, and ELISA examinations. Our data showed that compared with saline and heparin controls, monotherapy of simvastatin and the adjunctive therapy with simvastatin and heparin significantly improved the thrombus resolution and reduced inflammatory cells migration into the venous wall, the release of the inflammatory cell adhesion molecule (P-selectin), inflammatory chemokine (MCP-1) and pleiotropic proinflammatory cytokines (IL-6) into the blood, and the local expression of P-selectin and MCP-1 in the venous wall. Simvastatin targets anti-inflammatory pathways during the resolution phase of a thrombus, providing a therapeutic potential in DVT resolution and post-thrombotic syndrome prevention.

Inflammation in deep vein thrombosis: a therapeutic target?

“…Statin treatment was indeed reported to reduce the occurrence of DVT, [72] although these results are subject to debate in the literature [73]. Statins have also shown anti-inflammatory effects in rodent models of thrombosis, as evidenced by reductions in (i) the levels of several inflammatory biomarkers (including cytokines, sP-selectin), (ii) neutrophil and macrophage infiltrations, and (iii) levels of H3Cit within the thrombi [74] or the vessel wall [75]. Moreover, the observation of accelerated thrombus resolution and less DVT-induced vein wall scarring suggested that statins protect against the onset of PTS [74].…”

Cytokines, Adhesion Molecules, and Matrix Metalloproteases as Predisposing, Diagnostic, and Prognostic Factors in Venous Thrombosis

“…Inflammation as a target is responsible for parts of the effects of low molecular heparin as it is reducing TNF-α expression ( 93 ). Furthermore, statins have anti-inflammatory effects believed to be favourable for thrombosis resolution ( 94 – 97 ). Other modulations of the inflammatory response are explored in animal models as possible treatments.…”

Efficacy of simvastatin on carotid atherosclerotic plaque and its effects on serum inflammatory factors and cardiocerebrovascular events in elderly patients

“…Relevant basic experiments and clinical studies have confirmed that simvastatin effectively reduces and eliminates CAPs, and consequently decreases the incidence of acute cardiocerebrovascular events to improve the prognosis of patients ( 17 ). In addition, simvastatin exhibits an anti-inflammatory effect primarilu via mechanisms such as reduction of inflammatory infiltrating cell count, inhibition of adhesion molecule function on isopentenylated G protein and integrin, and reduction of CRP level ( 18 ). Currently, simvastatin is widely used in the clinical treatment of diseases such as cardiocerebrovascular diseases, atherosclerosis and myocardial ischemia ( 19 ).…”