Protein targets of inflammatory serine proteases and cardiovascular disease

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

The cardiovascular effects of proteolysis of high molecular weight basic fibroblast growth factor by inflammatory serine proteases

Abstract Cardiovascular disease is characterized by structural and functional changes of blood vessel's wall that lead to reduced blood flow and eventually occlusion. The integrity of the vascular wall is maintained by homeostatic mechanisms controlled by the endothelium. Stress caused by age, oxidants, mechanical injury, and inflammation can result in endothelial dysfunction leading to remodeling of the vessel wall. We found that thrombin, a key protease of the coagulation cascade and inflammatory response, cleaves the high molecular weight (HMW) forms of basic fibroblast growth factor (FGF-2), a ubiquitous protein with trophic effects on vascular cells. The C-terminal fragment of FGF-2 generated by thrombin is similar to low molecular weight (LMW; 18 kDa) FGF-2, and induces vascular cell activation of the mitogen-activated protein kinases ERK-1/2, migration and proliferation. The N-terminal fragment generated by thrombin cleavage of HMW FGF-2 contains a sequence rich in asymmetric-dimethyl-arginine (ADMA) residues. In free form ADMA inhibits key reactions for blood vessel homeostasis such as nitric oxide synthesis, and its serum levels, elevated in diabetes, renal failure, hypertension, and hypercholesterolemia, correlate with a poor prognosis in cardiovascular patients. We found that thrombin cleavage of HMW FGF-2 dramatically upregulates intracellular ADMA levels in cultured cells. Thus, the C-terminal cleavage product of HMW FGF-2 can activate intracellular signaling and control vascular cell functions, while the N-terminal fragment of FGF-2 generates ADMA, a powerful inhibitor of nitric oxide synthesis. We hypothesize that upon vascular injury HMW FGF-2 is processed by inflammatory serine proteases such as thrombin generating molecules that accelerate the development of intimal hyperplasia. This novel mechanism implicates human HMW FGF-2 in the pathogenetic mechanisms of vascular injury occurring in hypertension, diabetes, and dyslipidemia, conditions that are all characterized by elevated serum levels of ADMA. The elucidation of these mechanisms will foster the development of new pharmacological tools for the treatment of the cardiovascular disorders associated with these diseases

Does Heart Valve Team Risk Assessment Predict Outcomes after Transcatheter Aortic Valve Replacement?

AbstractConsideration for transcatheter aortic valve replacement (TAVR) necessitates an integrated risk assessment by members of the Heart Valve Team. The utility of the integrated risk assessment for predicting TAVR outcomes is not established. This article aims to compare the utility of the integrated risk assessment to that of the Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score for predicting patient outcomes after TAVR. A total of 274 patients who underwent TAVR from January 2016 to August 2017 were included in this study. Patients were deemed intermediate or high risk by two surgeons on the Heart Valve Team based on an integrated risk assessment that incorporates the STS-PROM score, fragility measures, end-organ dysfunction, and surgeon evaluation. Patients were also deemed low, intermediate, or high risk based solely on their STS-PROM scores of &lt;3%, ≥3% to &lt;8%, and ≥8%, respectively. Differences in postoperative outcomes between intermediate- and high-risk groups as categorized by the integrated risk assessment versus STS-PROM were compared. There were no statistically significant differences in postoperative outcomes between patients who were deemed high and intermediate risk by the Heart Valve Team risk assessment. In contrast, postoperative complication rates were significantly higher in patients deemed high risk as compared with intermediate risk by STS-PROM. Integrated risk assessment by the Heart Valve Team is not superior to STS-PROM in predicting postoperative outcomes in patients undergoing TAVR.</jats:p