Sirtuin 5 promotes arterial thrombosis by blunting the fibrinolytic system

Abstract

Aims Arterial thrombosis as a result of plaque rupture or erosion is a key event in acute cardiovascular events. Sirtuin 5 (SIRT5) belongs to the lifespan-regulating sirtuin superfamily and has been implicated in acute ischemic stroke and cardiac hypertrophy. This project aims at investigating the role of SIRT5 in arterial thrombus formation. Methods and Results Sirt5 transgenic (Sirt5Tg/0) as well as knock-out (Sirt5-/-) mice underwent photochemically-induced carotid endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) treated with SIRT5 silencing-RNA (si-SIRT5) as well as peripheral blood mononuclear cells (PBMCs) from acute coronary syndrome (ACS) patients and non-ACS controls (case-control study, total n = 171) were used to increase the translational relevance of our data. Compared to WT controls, Sirt5Tg/0 mice displayed accelerated arterial thrombus formation following endothelial-specific damage. Conversely, in Sirt5-/-mice arterial thrombosis was blunted. Platelet function was unaltered, as assessed by ex vivo collagen-induced aggregometry. Similarly, activation of the coagulation cascade as assessed by vascular and plasma tissue factor (TF) and TF pathway inhibitor (TFPI) expression was unaltered. Increased thrombus embolization episodes and circulating D-dimer levels suggested augmented activation of the fibrinolytic system in Sirt5-/- mice. Accordingly, Sirt5-/- mice showed reduced plasma and vascular expression of the fibrinolysis inhibitor plasminogen activator inhibitor (PAI)-1. In HAECs, SIRT5-silencing inhibited PAI-1 gene and protein expression in response to TNF-α. This effect was mediated by increased AMPK activation and reduced phosphorylation of the MAP kinase ERK 1/2, but not JNK and p38 as shown both in vivo and in vitro. Lastly, both PAI-1 and SIRT5 gene expression are increased in ACS patients compared to non-ACS controls after adjustment for cardiovascular risk factors, while PAI-1 expression increased across tertiles of SIRT5. Conclusions SIRT5 promotes arterial thrombosis by modulating fibrinolysis through endothelial PAI-1 expression. Hence, SIRT5 may be an interesting therapeutic target in the context of atherothrombotic events. Translational perspectives This study illustrates a novel role for Sirtuin 5 in arterial thrombosis by regulating fibrinolysis through plasminogen activator inhibitor 1 (PAI-1). These results shed new light onto the pathophysiology of arterial thrombus formation which underlies most of the acute atherosclerotic complications. Also, they further affirm the intrinsic relationship between lifespan regulating genes, vascular dysfunction and age-related cardiovascular disease, thus indicating these genes as potential targets for cardiovascular prevention and therapy. Further studies will be needed to assess the predictive ability of SIRT5 in patients with acute cardiovascular or cerebrovascular events. Also, the design of specific SIRT5 inhibitors will allow trials aiming at investigating the efficacy of SIRT5 blockage in the clinical setting.

Sirtuins as Interesting Players in the Course of HIV Infection and Comorbidities

“…Increased levels of circulating D-dimers and an increased incidence of thrombus embolization have been noted. The above results were confirmed in peripheral blood mononuclear cells of patients with acute coronary syndrome (ACS), which showed significantly higher expression of SIRT5 and PAI-1 compared to the control group without ACS [64]. Figure 3 schematically shows the participation of sirtuins and HIV infection in the development of cardiovascular disorders.…”

Associated Risk of Death from Covid-19 Infection in Patients with Hypertensive Co-Morbidities

“…The European Society of Cardiology (ESC), the American College of Cardiology (ACC), and the Canadian Cardiovascular Society (CCS) publish the latest treatment guidelines for hypertensive patients associated with the COVID-19 outbreak. The results of the publication were also adopted by the Indonesian Cardiovascular Specialist Association (PERKI), which was released on March 26, 2020 (Liberale et al, 2020). These three institutions state that, in humans, there has not been any link found between the use of ACEI or ARB with the increasing severity that occurs in patients.…”

Long-term dietary supplementation with plant-derived omega-3 fatty acid improves outcome in experimental ischemic stroke

“…Upon termination of the 12-month long dietary intervention, two different cohorts were set: one for baseline measurement including a total of 18 animals that were sacrificed and harvested without any interventions and another cohort which underwent transient middle cerebral artery occlusion (tMCAO) to induce cerebral ischemia/reperfusion. The cohort size was decided based on our previous experience with tMCAO 18,[20][21][22][23][24] . According to our power calculation, the minimal sample size request to detect a 30% decrease in stroke size with a power of 95% and two-sided alpha error of 5% was 12 animals per group.…”

“…After euthanasia, mice were perfused with 10 ml of phosphate buffered saline (PBS) and relevant organs were excised. Murine brains were cut into 5 equally spaced (2 mm) coronal sections by mean of a steel brain matrice and immersed in a 2% solution of 2,3,5triphenyltetrazolium chloride (TTC) (Sigma-Aldrich, Chemie GmbH, Buchs, Switzerland) at 37 °C for 20 min 18 . TTC is a redox indicator, which changes its colour from white to red, as it gets reduced to 1,3,5-triphenylformazan in viable tissues.…”

“…Given the increasing evidence suggesting ALA as a cardio-protective nutritional supplement and in consideration of the deep involvement of inflammation in ischemic stroke pathophysiology [16][17][18] , we hypothesized that plant-derived n-3 fatty acids may not only play a preventive role in stroke predisposition but also directly ameliorate its outcome. Therefore, this study investigated the effects of a long-term dietary intervention with the plant-derived n-3 fatty acid ALA on the outcome of ischemic stroke in old mice and the mechanisms pertaining to the observed effects.…”