Mechanisms of endothelial dysfunction in rheumatoid arthritis: lessons from animal studies

Abstract

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by articular and extra-articular manifestations involving cardiovascular diseases (CVDs), which account for 30% to 50% of all deaths. In patients with RA, atherosclerosis lesions occur earlier and have a more rapid evolution than in the general population. Beyond mortality, the impact of CVD on quality of life, combined with the associated increase in health-care costs, renders CVD in RA a major public health problem. Recent studies showed that patients with RA are characterized by the presence of endothelial dysfunction (ED), which is recognized as a key event in the development of atherosclerosis. By definition, ED is a functional and reversible alteration of endothelial cells, leading to a shift of the actions of the endothelium toward reduced vasodilation, proinflammatory state and proliferative and prothrombotic properties. Although the improvement of endothelial function is becoming an important element of the global management of patients with RA, the mechanistic determinants of ED in RA are still poorly understood. Animal models of RA provide the unique opportunity to unravel the pathophysiological features of ED in RA. The present review summarizes the available data on mechanisms underlying ED in animal models of RA and proposes attractive prospects in order to discover novel therapeutic strategies of RA-associated ED.

Figure 1

Endothelium-derived factors and normal endothelial function. ANG-II, angiotensin II; EDHF, endothelium-derived hyperpolarizing factor; ET-1, endothelin 1; NO, nitric oxide; PGI₂, prostacyclin; TXA₂, thromboxane A₂.

Figure 2

Schematic representation of the mechanisms involved in decreased nitric oxide (NO) production in endothelial cells from arthritic rats. Endothelial nitric oxide synthase (eNOS) catalyses the conversion of L-arginine to NO. The upregulation of arginase pathway and the deficit in the co-factor of eNOS tetrahydrobiopterin (BH₄) cause uncoupling of eNOS to generate superoxide anions (O₂^–) which subsequently scavenge NO to generate peroxynitrite (ONOO⁻). Angiotensin-II (ANG-II) might amplify O₂^– production by activating NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase after ANG-II type 1 (AT1) receptor activation. Up and down arrows indicate increases or decreases in amount or activity (from [14-23]).