Date Published: April 19, 2019
Publisher: Public Library of Science
Author(s): Ashok Kumar Gupta, Bhupinder Singh Chopra, Bhavna Vaid, Amin Sagar, Sachin Raut, Maulik D. Badmalia, Neeraj Khatri, Hugo ten Cate.
The present study provides first evidence on the role of plasma gelsolin in protecting pulmonary thromboembolism and thrombosis in a mouse model. Gelsolin is the most abundant actin depolymerizing protein in plasma and its significantly depleted values have been reported in metabolic disorders including cardiovascular diseases and myocardial infarction. Though gelsolin replacement therapy (GRT) has been shown to be effective in some animal models, no such study has been reported for thrombotic diseases that are acutely in need of bio-therapeutics for immediate and lasting relief. Here, using mice model and recombinant human gelsolin (rhuGSN), we demonstrate the antithrombotic effect of gelsolin in ferric chloride induced thrombosis in carotid artery and thrombin induced acute pulmonary thromboembolism. In thrombosis model, arterial occlusion time was significantly enhanced upon subcutaneous (SC) treatment with 8 mg of gelsolin per mice viz. 15.83 minutes vs. 8 minutes in the placebo group. Pertinently, histopathological examination showed channel formation within the thrombi in the carotid artery following injection of gelsolin. Fluorescence molecular tomography imaging further confirmed that administration of gelsolin reduced thrombus formation following carotid artery injury. In thrombin-induced acute pulmonary thromboembolism, mice pretreated with aspirin or gelsolin showed 100 and 83.33% recovery, respectively. In contrast, complete mortality of mice was observed in vehicle treated group within 5 minutes of thrombin injection. Overall, our studies provide conclusive evidence on the thrombo-protective role of plasma gelsolin in mice model of pulmonary thromboembolism and thrombosis.
Globally, cardiovascular and cerebrovascular diseases as well as venous thromboembolism are the cause of 17 million deaths annually and are projected to be the top two major causes of death by 2030. Considering the paucity of FDA-approved biotherapeutics for short- and long-term interventions, the cost of medical care for these conditions is immense and is increasing every year. Platelets play a crucial role in the pathogenesis of thrombosis[3, 4], essentially arterial and microvascular thrombi that in turn is accountable for vascular diseases[5, 6]. Presently, pharmacological approaches to treat these thromboembolic disorders focus on therapies utilizing anticoagulants such as heparin. Blood viscosity is known to increase in these cases due to “spillage” of F-actin in plasma due to local tissue injury and/or cell death. This further aggravates the condition by causing occlusions and sharply reduces the availability of natural anti-clotting agents.
With the increase in sedentary lifestyle, uncontrolled calorie and imbalanced nutritional intakes, metabolic disorders particularly cardiovascular, cerebrovascular diseases and venous thromboembolism are emerging as major pathological disorders responsible for high mortality in humans, thus significantly increasing the healthcare costs[1, 2]. Current treatment options for thrombosis are not adequate, therefore, there is a need for new biomolecules which can provide a long-lasting and holistic antithrombotic activity. Minimalistic approaches such as protein-analysis or cell-line based experiments provide useful information but can not substitute animal experimentation where it is important to understand the complete balance between biochemistry to tissue. Thus, we opted to perform animal experiments that provide a complete mapping of the disorder and intervention profile. As introduced, decreased gelsolin levels have been reported in many human diseases as well as in animal models. GRT is showing promising rescue in many conditions and thus is under clinical trials for different critical care indications. More relevant to our work, administration of recombinant gelsolin has been shown to have a protective effect in murine stroke. It correlates with long-term tracking of response and quality-adjusted life of stroke patients with their plasma gelsolin levels. Interconnecting the therapeutic promise of GRT, and its potential role in maintaining cardiovascular balance, we carried out animal studies to examine the antithrombotic activity of gelsolin.
We for the first time report the thrombo-protective capability of exogenous gelsolin in ferric chloride-induced thrombosis of carotid artery and thrombin induced acute pulmonary thromboembolism in mice. The mechanism involved in this pGSN–mediated protection, however, requires further investigation, but it opens up the possibility of GRT as a thrombo-protective option.