Carbon monoxide releasing molecule-2 attenuates angiotensin II-induced IL-6/Jak2/Stat3-associated inflammation by inhibiting NADPH oxidase- and mitochondria-derived ROS in human aortic smooth muscle cells

Abdominal aortic aneurysm (AAA) is a common inflammatory vascular disease. Angiotensin II (Ang II) involves in AAA progression by promoting the proliferation and migration of vascular smooth muscle cells, the degra-dation of extracellular matrices, and the generation of ROS to lead to vascular inflammation. Carbon monoxide releasing molecule-2 (CORM-2) is known to exert anti-inflammatory and antioxidant activities. However, it remains unclear whether CORM-2 can suppress Ang II-induced vascular inflammation to prevent AAA pro-gression. Therefore, this study aimed to investigate the vasoprotective effects of CORM-2 against Ang II-induced inflammatory responses of human aortic smooth muscle cells (HASMCs) and the underlying mechanisms of those effects. The results showed that Ang II induced inflammatory responses of HASMCs via NADPH oxidase-and mitochondria-derived ROS/NF-kappa B/IL-6/Jak2/Stat3 pathway which was attenuated by the pretreatment with CORM-2. Additionally, CORM-2 further exhibited anti-inflammatory activities in Ang II-stimulated HASMCs, as indicated by the reduction of monocyte adhesion to HASMCs and migration of HASMCs via the suppression of ICAM-1 and VCAM-1 as well as MMP-2 and MMP-9 levels, respectively. Moreover, Ang II-induced COX-2-mediated PGE(2) secretion was also inhibited by the pretreatment with CORM-2. Importantly, our data demon-strated that CORM-2 reversed Ang II-induced IL-6 overexpression dependent on Nrf2 activation and HO-1 expression. Taken together, the present study indicates that CORM-2-induced Nrf2/HO-1 alleviates IL-6/Jak2/Stat3-mediated inflammatory responses to Ang II by inhibiting NADPH oxidase-and mitochondria-derived ROS, suggesting that CORM-2 is a promising pharmacologic candidate to reverse the pathological changes involved in the inflammation of vessel wall for the prevention and treatment of AAA.

Automated summary

The study found that CORM-2 can inhibit Ang II-induced inflammatory responses and alleviate the proliferation, migration, and inflammation of vascular smooth muscle cells. In addition, CORM-2 also reduces monocyte adhesion and cell migration by inhibiting specific molecules and signaling pathways. The results of the study also suggest that CORM-2 can reverse Ang II-induced IL-6 overexpression by activating Nrf2 and HO-1.