Current Drug Targets - Cardiovascular & Hematological Disorders - Volume 1, Issue 2, 2001

The balance between the activities of the coagulation and fibrinolytic cascades is crucial for normal hemostasis. However, imbalances can lead to pathological thrombotic events, as is observed in heart attacks and strokes, as well as excessive bleeding, as in hemophilia. Recent investigations have uncovered a novel molecular connection between the two cascades that has been termed thrombin-activable fibrinolysis inhibitor (TAFI) as well as procarboxypeptidase U, procarboxypeptidase R or plasma procarboxypeptidase B. TAFI is the precursor of an enzyme (TAFIa) with basic carboxypeptidase activity that attenuates the lysis of fibrin clots by removal of the carboxyl-terminal lysine residues from partially-degraded fibrin that mediate positive feedback in the fibrinolytic cascade. The plasma concentration of TAFI varies substantially (up to ~10-fold) in the human population and may constitute a novel risk factor for thrombotic disorders. Sixteen single nucleotide polymorphisms have been identified in the 5'-flanking, protein coding, and 3'-untranslated regions of the TAFI gene. The polymorphisms all have been shown to be associated with variations in plasma TAFI concentrations. One amino acid substitution has been found to directly alter the properties of the TAFIa enzyme. This review provides a general overview of the TAFI pathway, including a discussion of the spectrum of inhibitors of TAFIa that have been described, and summarizes the recent advances in the molecular genetics of the TAFI gene as well as the results of studies that may implicate the TAFI pathway in risk for arterial and venous thrombotic disorders.

Changes in cardiovascular tissue structure can result in alterations in function. This process occurs as a continuum and can be defined as cardiovascular remodeling. A family of zinc dependent proteases known as the matrix metalloproteinases (MMPs) has been demonstrated to cause tissue remodeling. A number of past studies have demonstrated increased expression and activation of MMPs in both myocardial and vascular remodeling processes. Experimental results support the concept that the MMPs directly contribute to progressive myocardial remodeling post-myocardial infarction and in cardiomyopathic disease. Within the vascular compartment, compelling evidence exists for the contributory role of MMPs in atheromatous plaque rupture and aortic aneurysms. Therefore, the purpose of this review is to examine recent studies of this proteolytic system in the context of cardiovascular remodeling.

Human apolipoprotein E (apoE) consists of a single polypeptide chain with 299 amino acids and is best known for its role in the transport of cholesterol and other lipids between peripheral tissues and the liver. However, more direct effects of apoE on the vascular wall may well contribute to arterial protection from atherosclerosis. This review will focus on: (a) the ability of apoE to direct cholesterol efflux mechanisms with the aid of apoA1 and the ATP binding cassette transporter 1 (ABC1) (b) the ability of apoE to prevent platelet aggregation by facilitating the production of endogenous nitric oxide (NO) (c) the ability of apoE to inhibit the proliferation of T-lymphocytes by internalization of the IL-2 receptor and (d) the ability of apoE to inhibit proliferation of endothelial cells by out competing growth factors for interaction with cell surface heparan sulfate proteoglycans (HSPG's). The characterization of apoE and its many functions has provided insight into the ultimate potential of this protein as a possible therapeutic agent for the treatment of atherosclerosis. This review will examine key scientific advances, which focus on possible therapeutic strategies that encompass the use of apoE in the amelioration of atherosclerosis.

Insulin resistance and hyperinsulinemia are the critical characteristics of the metabolic syndrome that is associated with abdominal obesity and are the early manifestations of its progression to type 2 diabetes. These metabolic abnormalities are becoming recognized as a major contributor to cardiovascular disease. The experimental studies required to elucidate the underlying mechanisms and to develop effective preventative strategies will require the use of appropriate animal models and these are available. The evidence from such research indicates that a wide range of interventions (including peroxisome proliferator activator receptor agonists, insulin-sensitizing agents, statins, fibrates, angiotensin-converting enzyme inhibitors, estrogen receptor modulators, lipid-based nutriceuticals, and ethanol) can markedly reduce or prevent vasculopathy and ischemic cardiac lesions in animal models. Overall, the results suggest that early damage to the vascular wall, both in function and presenting as atherosclerotic lesions, is secondary to long-term hyperinsulinemia and, especially, to postprandial peaks in plasma insulin levels, and is exacerbated by the accompanying hyperlipidemia. Effective treatment will, of necessity, be preventative and will necessitate diagnostic approaches that can identify asymptomatic individuals at high risk for vascular damage and eventual progression to type 2 diabetes. Therapeutic targets in this population include insulin sensitivity and the associated signal transduction pathways, the peroxisome proliferator activator receptor-α and -γ systems, and the complex pathways leading from acetyl CoA and the citric acid cycle to the synthesis of fatty acid and the storage of triglyceride. These pharmacological approaches offer the prospect of preventing a significant proportion of cardiovascular disease.