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Non-steroidal anti-inflammatory drugs (NSAIDs) represent a clinically important class of agents. NSAIDs are commonly used in treatment of conditions such as headache, fever, inflammation and joint pain. Complications often arise from chronic use of NSAIDs. Gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulcerations and GI bleeds limit usage of NSAIDs. These toxicities are thought to be due to cyclooxygenase (COX)-1 blockade. COX-1 generates cytoprotective prostanoids such as prostaglandin (PG) E2 and prostacyclin (PGI2). COX-2 inhibitors, commonly referred to as coxibs, were developed to inhibit inflammatory prostanoids without interfering with production of COX-1 prostanoids. Concerns over cardiovascular safety, however, have evolved based on the concept of inhibition of COX-2-derived endothelial prostanoids without inhibition of platelet thromboxane A2, leading to increased cardiovascular risk. The Celecoxib Long-Term Arthritis Safety Study (CLASS) trial did not show a significant increase in cardiovascular risk for celecoxib (Celebrex), but results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study showed an increased cardiovascular risk with long-term daily usage of rofecoxib in patients with rheumatoid arthritis. The Adenomatous Poly Prevention on Vioxx (APPROVe) trial further evaluated cardiovascular effects of rofecoxib and recently led to removal of this drug from the marketplace. Coxibs affect renal function via blockade of normal COX-2 functions. COX-2 expression increases in high renin states and in response to a high-sodium diet or water deprivation. PGI2 and PGE2 are the most important renal prostanoids. PGI2 inhibition results in hyperkalemia. PGE2 inhibition results in sodium retention, which leads to hypertension, peripheral edema and potentially exacerbation of heart failure. This review article discusses beneficial and deleterious effects associated with prostanoids produced by COX-1 and COX-2 in various organs and how blockade of these products translates into clinical medicine.

Integrins are the principle mediators of molecular dialog between a cell and its extracellular matrix environment. The unique combinations of integrin subunits determine which extracellular matrix molecules are recognized by a cell. Recent studies have demonstrated that remodeling in heart and vasculature is linked to alterations in extracellular matrix and integrin expression. The roles of integrins in controlling cellular behavior have made these molecules highly attractive drug targets. New insights into mechanisms whereby the extracellular matrix takes part in the control of smooth muscle cell proliferation and cardiac growth suggest a number of putative targets for future therapies that can be applied to increase plaque stability, prevent the clinical consequences of atherosclerosis and improve outcomes after interventional procedures such as cardiac transplantation. Therapeutic candidates include antibodies, cyclic peptides, peptidomimetics and small molecules. The integrin inhibitors Integrilin and ReoPro have been approved as blood thinners in cardiovascular disease, and newer agents are undergoing testing. Although integrin function is important in the cardiovascular system, there are wide gaps in knowledge. In this review, we discuss the primary mechanisms of action and signaling of integrins in the cardiac and vascular system in normal and pathological states, as well as therapeutic strategies for targeting these molecules in the cardiovascular system.

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