Intermedin _{1− 53} Attenuates Abdominal Aortic Aneurysm by Inhibiting Oxidative Stress

Abstract

Objective-Oxidative stress plays a critical role in the development of abdominal aortic aneurysm (AAA). Intermedin (IMD) is a regulator of oxidative stress. Here, we investigated whether IMD reduces AAA by inhibiting oxidative stress. Approach and Results-In angiotensin II-induced ApoE −/− mouse and CaCl 2 -induced C57BL/6J mouse model of AAA, IMD 1−53 significantly reduced the incidence of AAA and maximal aortic diameter. Ultrasonography, hematoxylin, and eosin staining and Verhoeff-van Gieson staining showed that IMD 1−53 significantly decreased the enlarged aortas and elastic lamina degradation induced by angiotensin II or CaCl 2 . Mechanistically, IMD 1−53 attenuated oxidative stress, inflammation, vascular smooth muscle cell apoptosis, and matrix metalloproteinase activation. IMD 1−53 inhibited the activation of redox-sensitive signaling pathways, decreased the mRNA and protein expression of nicotinamide adenine dinucleotide phosphate oxidase subunits, and reduced the activity of nicotinamide adenine dinucleotide phosphate oxidase in AAA mice. Expression of Nox4 was upregulated in human AAA segments and in angiotensin II-treated mouse aortas and was markedly decreased by IMD 1−53 . In vitro, vascular smooth muscle cells with small-interfering RNA knockdown of IMD showed significantly increased angiotensin II-induced reactive oxygen species, and small-interfering RNA knockdown of Nox4 markedly inhibited the reactive oxygen species. IMD knockdown further increased the apoptosis of vascular smooth muscle cells and inflammation, which was reversed by Nox4 knockdown. Preincubation with IMD 17−47 and protein kinase A inhibitor H89 inhibited the effect of IMD 1-53 , reducing Nox4 protein levels. Conclusions-IMD

Calcitonin gene‐related peptide inhibits angiotensin II‐induced NADPH oxidase‐dependent ROS via the Src/STAT3 signalling pathway

“…For instance, in an animal model of Ang II‐induced hypertension, RAMP1 transgenic mice were shown to be protected from increases in their SBP 24 . However, the CGRP and/or CGRP receptor expression profile varies with the state and stage of the disease, including that in the Ang II‐induced model 25,26 . In addition, the change in CGRP receptor expression was suggested to further amplify the responses to CGRP, especially in the hypertension model 27 .…”

Aortic Aneurysms

“…Intermdedin1–53, a product of prepro-intermedin, reduced AngII or calcium chloride-induced AAA in mice. 78 This preventive effect on AAA was associated with attenuation of oxidative stress in AAA.…”

Intermedin1-53 attenuates aging-associated vascular calcification in rats by upregulating sirtuin 1

“…Our previous research showed that exogenous IMD1-53 may attenuate CKD-associated vascular calcification by upregulating α-klotho and vitamin D3 plus nicotine (VDN)-induced vascular calcification by increasing MGP in young rats [6,7]. In addition, IMD1-53 treatment could improve vascular function by increasing endothelial nitric oxide synthase activity [25] and inhibiting reactive oxygen species production [26], which may affect vascular aging [4]. However, whether IMD inhibits aging-associated vascular calcification is unclear.…”