Protein targets of inflammatory serine proteases and cardiovascular disease

Abstract

Serine proteases are a key component of the inflammatory response as they are discharged from activated leukocytes and mast cells or generated through the coagulation cascade. Their enzymatic activity plays a major role in the body's defense mechanisms but it has also an impact on vascular homeostasis and tissue remodeling. Here we focus on the biological role of serine proteases in the context of cardiovascular disease and their mechanism(s) of action in determining specific vascular and tissue phenotypes. Protease-activated receptors (PARs) mediate serine protease effects; however, these proteases also exert a number of biological activities independent of PARs as they target specific protein substrates implicated in vascular remodeling and the development of cardiovascular disease thus controlling their activities. In this review both PAR-dependent and -independent mechanisms of action of serine proteases are discussed for their relevance to vascular homeostasis and structural/functional alterations of the cardiovascular system. The elucidation of these mechanisms will lead to a better understanding of the molecular forces that control vascular and tissue homeostasis and to effective preventative and therapeutic approaches.

Pathway‐selective antagonism of proteinase activated receptor 2

“…Inhibitors of specific proteases have successfully progressed through the clinic (Leung et al, 2000;Abbenante and Fairlie, 2005;Turk, 2006). However, many proteases are involved in most diseases and each protease usually has pleiotropic functions in both normal physiology and disease (Cudic and Fields, 2009;Pejler et al, 2010;Sharony et al, 2010;Moore and Crocker, 2012). A common cellular target of several proteases, as well as more selective modulation of the functions induced by proteases, may be necessary for more specific and more effective drugs.…”

Dual inhibition of cathepsin G and chymase reduces myocyte death and improves cardiac remodeling after myocardial ischemia reperfusion injury

“…However, some evidence indicates that ISPs may also be key regulators of the inflammatory response [2, 24]. ISPs cleave and functionally modulate a number of protein substrates, including clotting factors, neutrophil chemoattractants, and extracellular (ECM) components (e.g., proteoglycans, collagen, elastin, fibronectin) [35, 40]. The adverse effects of Cat.G and chymase go beyond the breakdown of matrix proteins or the generation of cytokines and chemokines, which stimulate the infiltration of inflammatory cells.…”

Protease activity of Per a 10 potentiates Th2 polarization by increasing IL‐23 and OX40L

“…Proteases from sources like house dust mite (Der p 1, Der p 3, Der p 6, Der p 9, Der f 1) and fungi (Asp f 13, Pen c 1, Pen c 13, Epi p 1) have been characterized as potent allergens [4]. Protease allergens act by proteolytic cleavage of an array of cell surface molecules and are known to modulate the functions of a variety of cell types including both immune and structural cells [5]. Proteolytic allergens from house dust mite are known to exacerbate allergic immune responses by selective cleavage of CD23, CD25, DC-SIGN, and DC-SIGNR on surface of immune cells Correspondence: Dr. Naveen Arora e-mail: naveen@igib.res.in; navdelhi@hotmail.com [6,7].…”