Catestatin prevents endothelial inflammation and promotes thrombus resolution in acute pulmonary embolism in mice

Abstract

Catestatin (CTS), a catecholamine-release inhibitory peptide, exerts pleiotropic cardiac protective effects. Pulmonary embolism caused by deep vein thrombosis involving vascular dysfunction. The present study aims to investigate the effects of CTS on thrombus formation that may inhibit the development of pulmonary embolism and its potential pathway. Acute pulmonary embolism (APE) model was developed as an in vivo model. The effects of CTS on mice with APE were examined. Human pulmonary artery endothelial cells (HPAECs) were pretreated with CTS before thrombin stimulation, and endothelial inflammation and underlying mechanisms were evaluated in vitro. That plasma CTS level was decreased in APE mice, while the number of platelets was significantly increased. The decreased circulating CTS level negatively associated with the number of platelets. CTS administration increased the survival rate of APE mice and protected against microvascular thrombosis in lung. APE-induced the increase in platelets number and plasma von Willebrand factor (VWF) were inhibited by CTS. Platelets from CTS-treated APE mice showed impaired agonist-induced platelets aggregation and spreading. CTS also ameliorated APE-induced the systemic inflammatory response. In in vivo study, thrombin-induced the increase in inflammation, TLR-4 expression and p38 phosphorylation were abrogated by CTS in HPAECs. Furthermore, TLR-4 overexpression inhibited the effect of CTS on VWF release and inflammation in HPAECs. Collectively, CTS increases thrombus resolution by attenuating endothelial inflammation at partially via inhibiting TLR-4-p38 pathway. The present study may provide a novel approach for anti-thrombosis.

The immunosuppression of macrophages underlies the cardioprotective effects of catestatin (CST)

“…2E). These findings show that CST is both necessary and sufficient for restoring immune homeostasis in accordance with CST's role as an anti-inflammatory peptide (23)(24)(25)(26).…”

Serum Catestatin Levels and Arterial Stiffness Parameters Are Increased in Patients with Inflammatory Bowel Disease

“…Since the physiological effects of norepinephrine and SNS mediators promote tachyphylaxis and systemic vasoconstriction it is possible that these effects contributed to detrimental vascular remodeling as evident in increased arterial stiffness parameters. Finally, although CST stand-alone generally confers protective effects on heart and vasculature, as shown in a handful of previous studies [22,23,60,61], it is possible that in the setting of IBD, a disease state characterized by persistent inflammation and increased SNS activity, effects of CST, despite being elevated in circulation, are not sufficient to compensate for adverse arterial remodeling that is propagated by the proinflammatory and adrenergic cellular pathways. However, due to a substantial evidence gap in this regard and lack of studies reporting on CST and arterial stiffness parameters, these hypothetical interactions need to be confirmed in future preclinical and mechanistic studies.…”

“…Studies implicate its connection with multiple functions throughout various systems, including vasodilatation [13], immunoregulation [14], insulin resistance [15][16][17], antimicrobial effect [18,19] and obstructive sleep apnea [20]. Furthermore, it has been reported to be a key regulator of cardiovascular function, with cardioprotective effects including exhibiting the trough suppression of atherosclerosis [21], negative inotropic and lusitropic cardiac effects [22], inhibition of coronary vasoconstriction [21], a reduction in oxidative stress in ischemic-reperfused myocardium [22], a decrease in endothelial inflammation and regulation of blood pressure [10,[23][24][25]. CST is believed to have an important role in the pathophysiology of hypertension, heart failure, reperfusion injury and coronary heart disease [25][26][27].…”

Role of Catestatin in the Cardiovascular System and Metabolic Disorders

“…A recent study involving an in vivo and in vitro approach investigated Cts in acute pulmonary embolism ( 99 ). Its administration in mice with this pathology increased survival as well as augmented thrombus resolution by attenuating endothelial inflammation ( 99 ).…”

“…In summary, based on in vitro and in vivo animal models, it was demonstrated that Cts exhibits a potential cardioprotective effect by acting directly as a cardiodepressing peptide through multiple signaling pathways ( 52 , 53 , 88 – 90 ), it may also reduce apoptosis of cardiomyocytes induced by oxidative stress ( 67 , 92 – 96 ), and is beneficial in acute pulmonary embolism ( 99 ). However, more studies are needed in these areas, in particular, regarding Cts in I/R injury of the heart ( 67 , 92 – 97 ).…”