AT₁ receptor characteristics of angiotensin analogue binding in human synovium

Abstract

Angiotensin II (AII) reduces blood flow, modulates vascular remodelling and is a growth factor. Human inflammatory arthritides are characterized by synovial hypoperfusion, hypoxia and proliferation. We aimed to localize and characterize receptors for AII in human synovium. We used quantitative in vitro receptor autoradiography with [125I]‐(Sar1, Ile8)AII and [125I]‐AII on human synovium from patients with chondromalacia patellae, osteoarthritis and rheumatoid arthritis. [125I]‐(Sar1, Ile8)AII and [125I]‐AII bound to similar sites on synovial blood vessels, lining cells and stroma. Binding to microvessels (< 100 μm diameter) was more dense than to arteriolar media, and vascular binding was more dense than that to lining cells and stroma. Microvessels and arterioles which displayed angiotensin converting enzyme‐like immunoreactivity also displayed specific binding of [125I]‐(Sar1, Ile8)AII. Specific binding of [125I]‐(Sar1, Ile8)AII to each structure was completely inhibited by 10 μm dithiothreitol and was inhibited by unlabelled ligands with the rank order of potency (Sar1, Ile8)AII > AII > losartan = SKF108566 > PD123319 indicating an AT1 subclass of angiotensin receptor. GTPγS (1 μm) abolished specific binding of [125I]‐AII and abolished the high affinity component of the binding inhibition curve for AII against [125I]‐(Sar1, Ile8)AII, indicating G protein coupling. The distribution of [125I]‐(Sar1, Ile8)AII binding sites was similar in all disease groups and no significant differences in binding densities, affinities or specificities were observed between disease groups. Locally generated AII may act on synovial AT1 receptors to modulate synovial perfusion and growth. Specific AT1 receptor antagonists should help elucidate the role of angiotensins in human arthritis.

Ramipril and haloperidol as promising approaches in managing rheumatoid arthritis in rats

“…Angiotensin II produced from ACE in the activated RAS was reported to exert pro-inflammatory potential, at least via stimulation of angiotensin receptor type 1 (AT-1 receptor) in leukocytes (da Silveira et al, 2010;Chang and Wei, 2015). Earlier, Walsh et al (1994) stated that locally generated angiotensin II may act on synovial AT-1 receptors, thus modulating synovial perfusion and growth. RAS activation was also reported to be associated with oxidative stress and inflammatory progression through NADPH oxidase pathway (de Cavanagh et al, 2011;Kossmann et al, 2014;Passaglia et al, 2015).…”

Association of angiotensin-converting enzyme (ACE) gene insertion–deletion polymorphism with spondylarthropathies

“…ACE is produced by endothelium and mononuclear cells of macrophage origin, and ACE activity is significantly increased in patients with inflammatory arthritis compared to subjects with noninflammatory arthritis [31]. It has been postulated that locally generated angiotensin acts on synovial angiotensin receptors to modulate synovial perfusion and growth [32]. The D-allele of ACE gene polymorphism has been associated with higher plasma and tissue levels of ACE [25].…”

Peptide Hormone Regulation of Angiogenesis

“…The contribution of RAS to the pathology of rheumatoid arthritis is suggested by the observations that ANG II has proinflammatory effects (476), that ACE, ANG II, and AT1 receptors are upregulated in synovial tissue from experimental arthritis (446) or from patients with rheumatoid arthritis (589,590), and that targeting the angiotensin pathway with ACE blockers and AT1 inhibitors attenuates experimental arthritis (121, 479) and human inflammatory synovitis (446). Blockers of ACE activity may exacerbate inflammation by preventing the breakdown of BK.…”