Calcitonin gene-related peptide inhibits angiotensin II-induced NADPH oxidase-dependent ROS via the Src/STAT3...

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Pharmacology

Background:

• Calcitonin gene-related peptide (CGRP) is known to suppress oxidative stress and vascular smooth muscle cell (VSMC) proliferation.
• CGRP has demonstrated protective effects against angiotensin II (Ang II)-induced hypertension, vascular hypertrophy, and oxidative stress.

Purpose of the Study:

• To elucidate the underlying mechanism by which CGRP exerts its antioxidative effects in the context of Ang II-induced oxidative stress.
• To investigate the role of the Src/STAT3 signaling pathway in CGRP's protective actions against Ang II-induced vascular pathologies.

Main Methods:

• In vitro studies using Ang II-stimulated VSMCs to assess reactive oxygen species (ROS) generation and NADPH oxidase activity.
• Investigated the impact of CGRP on the activation of Src and STAT3 signaling pathways.
• Utilized constitutively active Src or STAT3, and specific inhibitors (H-89, CGRP8-37) to determine pathway dependency.
• In vitro and in vivo analyses of VSMC proliferation and hypertrophy.

Main Results:

• CGRP significantly suppressed ROS generation by NADPH oxidase in Ang II-induced VSMCs.
• CGRP abrogated the Ang II-stimulated activation of Src and STAT3.
• The antioxidative effect of CGRP was abolished upon expression of constitutively activated Src or STAT3.
• Inhibition of CGRP signaling pathways (H-89, CGRP8-37) blocked CGRP's protective effects against Ang II-induced oxidative stress.
• CGRP treatment inhibited Ang II-induced VSMC proliferation and hypertrophy, correlating with reduced ROS generation.

Conclusions:

• CGRP exerts its antioxidative effects by inhibiting the Src/STAT3 signaling pathway.
• This pathway is critically involved in Ang II-induced VSMC hypertrophy and hyperplasia.
• CGRP represents a potential therapeutic target for managing hypertension and associated vascular complications.