Elsevier

Pharmacology & Therapeutics

Volume 127, Issue 3, September 2010, Pages 295-314
Pharmacology & Therapeutics

Associate Editor: G.F. Baxter
TNFα in atherosclerosis, myocardial ischemia/reperfusion and heart failure

https://doi.org/10.1016/j.pharmthera.2010.05.002Get rights and content

Abstract

TNFα is crucially involved in the pathogenesis and progression of atherosclerosis, myocardial ischemia/reperfusion injury and heart failure. The formation and release of TNFα and its downstream signal transduction cascade following activation of its two receptor subtypes is characterized, with special emphasis on the cardiovascular system.

In the vasculature, TNFα alters endothelial and vascular smooth muscle cell function as well as endothelial cell–blood cell interaction; the importance of such alterations for vascular dysfunction, the initiation and progression of atherosclerosis are discussed.

In the myocardium, TNFα contributes to reversible and irreversible ischemia/reperfusion injury, post-myocardial infarction remodeling and heart failure development. Simultaneously, TNFα also contributes to cardioprotection by ischemic conditioning. Emphasis is placed on such ambivalent (detrimental vs. beneficial) role of TNFα, which appears to be dose- and time-dependent and in part related to the activation of the specific receptor subtype. Given the ambivalent role of TNFα and its receptors, it is not surprising that clinical trials using compounds that antagonize TNFα revealed ambiguous and largely disappointing results in cardiovascular disease, notably in heart failure.

Future perspectives to antagonize and/or potentially recruit TNFα in the cardiovascular system are critically discussed.

Section snippets

Tumor necrosis factor alpha: its formation, release and receptors

In 1975, tumor necrosis factor alpha (TNFα, cachexin or cachectin) was discovered as a circulating factor which can cause necrosis of tumors (Carswell et al., 1975).

More recently, TNFα has been identified as part of the innate immune system response to different forms of stresses [infection, trauma, ischemia/reperfusion (I/R)]. The innate immune system response is initiated independently from a specific antigen, and it uses pattern recognition receptors which when stimulated activate nuclear

Vascular effects of tumor necrosis factor alpha

The TNFα-mediated vascular dysfunction involves alterations in endothelial metabolism and function, platelet aggregation and EC–blood cell interaction, and in vascular smooth muscle cell (VSMC) function and proliferation (McKellar et al., 2009).

Tumor necrosis factor alpha and myocardial function

In healthy individuals, both the circulating and the cardiac TNFα concentrations are low (Aker et al., 2003, Arras et al., 1996, Frangogiannis et al., 1998). Supporting the notion that TNFα is of little physiological importance in the heart, TNFα-, TNFR1- and TNFR2 KO mice develop normally and have no discernable morphological or functional cardiac defects (Kurrelmeyer et al., 2000, Marino et al., 1997). Higher TNFα concentrations, however, alter myocardial function. Exogenous TNFα results in a

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