Homocysteine directly interacts and activates the angiotensin II type I receptor to aggravate vascular injury

Abstract

Hyperhomocysteinemia (HHcy) is a risk factor for various cardiovascular diseases. However, the mechanism underlying HHcy-aggravated vascular injury remains unclear. Here we show that the aggravation of abdominal aortic aneurysm by HHcy is abolished in mice with genetic deletion of the angiotensin II type 1 (AT1) receptor and in mice treated with an AT1 blocker. We find that homocysteine directly activates AT1 receptor signalling. Homocysteine displaces angiotensin II and limits its binding to AT1 receptor. Bioluminescence resonance energy transfer analysis reveals distinct conformational changes of AT1 receptor upon binding to angiotensin II and homocysteine. Molecular dynamics and site-directed mutagenesis experiments suggest that homocysteine regulates the conformation of the AT1 receptor both orthosterically and allosterically by forming a salt bridge and a disulfide bond with its Arg167 and Cys289 residues, respectively. Together, these findings suggest that strategies aimed at blocking the AT1 receptor may mitigate HHcy-associated aneurysmal vascular injuries.

Allosteric modulation of the catalytic VYD loop in Slingshot by its N-terminal domain underlies both Slingshot auto-inhibition and activation

“…D, intramolecular BRET of the SSH2-FlAsH biosensors in response to NRG stimulation (50 ng/ml NRG, 40 min). The BRET biosensor of the AT1R was used as a negative control (59). The SSH2-23-FlAsH, SSH2-63-FlAsH, and AT1R-FlAsH (23) were transiently transfected in MCF-7 cells, starved for 2 h, and then stimulated with 50 ng/ml NRG or control vehicle for 40 min.…”

Homocysteine Promotes Migration of Adventitial Fibroblasts via Angiotensin II type 1 Receptor Activation to Aggravate Atherosclerosis

“…10 Recent data have demonstrated that Hcy directly interacted and activated with AT1R to aggravate adventitial in ammation, collagen accumulation, and vascular injury. 1,2,9 However, little is known about the possible mechanisms by which Hcy can promote AFs migration and invasion and accelerate atherosclerosis formation via AT1R activation. This study revealed that Hcy induced AFs migration and invasion, which was inhibited with telmisartan treatment, an AT1R inhibitor.…”

“…Hcy is a nonessential sulfur-containing amino acid derived from the essential amino acid methionine and actively participates in various biochemical reactions. 1 HHcy (circulating Hcy ≥ 15 µ m) is an independent risk factor for many cardiovascular diseases, such as atherosclerosis, coronary heart disease, and abdominal aortic aneurysm. Although there is evidence that HHcy can cause vasodilation, damage endothelial cells, promote intravascular proliferation, promote outer membrane activation, and disrupt hemostasis/coagulation, [2][3][4][5] the mechanism by which Hcy aggravates atherosclerosis remains elusive.…”

“…6,7 Genetic deletion of AT1R effectively prevents pathological vascular injuries in various animal models, such as models hypertension and atherosclerosis. 8 Although recent studies indicate Hcy directly interacts and activates AT1R to aggravate vascular injury 1 and Hcy accelerates collagen accumulation in the adventitia of balloon-injured rat carotid arteries via AT1R expression, 9 little is known about the association between Hcy and AT1R in atherosclerosis.…”

Nuclear magnetic resonance to study the interactions acting in the enantiomeric separation of homocysteine by capillary electrophoresis with a dual system of γ‐cyclodextrin and the chiral ionic liquid EtCholNTf2

“…Homocysteine (Hcy) is a thiol containing non‐protein amino acid involved in methionine´s metabolism that is considered a biomarker of cardiovascular and neurodegenerative diseases . Few works reported the chiral separation of Hcy by HPLC and only two works employed CE for this purpose .…”