CO-releasing molecules CORM2 attenuates angiotensin II-induced human aortic smooth muscle cell migration through inhibition of ROS/IL-6 generation and matrix metalloproteinases-9 expression

Abstract

Ang II has been involved in the pathogenesis of cardiovascular diseases, and matrix metalloproteinase-9 (MMP-9) induced migration of human aortic smooth muscle cells (HASMCs) is the most common and basic pathological feature. Carbon monoxide (CO), a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory effects in various tissues and organ systems. In the present study, we aimed to investigate the effects and underlying mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on Ang II-induced MMP-9 expression and cell migration of HASMCs. Ang II significantly up-regulated MMP-9 expression and cell migration of HASMCs, which was inhibited by transfection with siRNA of p47phox, Nox2, Nox4, p65, angiotensin II type 1 receptor (AT1R) and pretreatment with the inhibitors of NADPH oxidase, ROS, and NF-κB. In addition, Ang II also induced NADPH oxidase/ROS generation and p47phox translocation from the cytosol to the membrane. Moreover, Ang II-induced oxidative stress and MMP-9-dependent cell migration were inhibited by pretreatment with CORM-2. Finally, we observed that Ang II induced IL-6 release in HASMCs via AT1R, but not AT2R, which could further caused MMP-9 secretion and cell migration. Pretreatment with CORM-2 reduced Ang II-induced IL-6 release. In conclusion, CORM-2 inhibits Ang II-induced HASMCs migration through inactivation of suppression of NADPH oxidase/ROS generation, NF-κB inactivation and IL-6/MMP-9 expression. Thus, application of CO, especially CORM-2, is a potential countermeasure to reverse the pathological changes of various cardiovascular diseases. Further effects aimed at identifying novel antioxidant and anti-inflammatory substances protective for heart and blood vessels that targeting CO and establishment of well-designed in vivo models properly evaluating the efficacy of these agents are needed.

The role of CORM-2 as a modulator of oxidative stress and hemostatic parameters of human plasma in vitro

“…These results are consistent with other studies on the role of CO donors in protecting against oxidative stress, i.e. studies of Tsai et al [ 8 ] demonstrated that CORM-2 inhibits angiotensin II-induced human aortic smooth muscle cells migration through inactivation of NADPH oxidase/reactive oxygen species generation. Babu et al [ 14 ] also noted that CORM-2 shows antioxidant property in murine intestinal epithelial MODE-K cells under oxidative stress (induced by H 2 0 2 ).…”

“…Babu et al [ 14 ] also noted that CORM-2 shows antioxidant property in murine intestinal epithelial MODE-K cells under oxidative stress (induced by H 2 0 2 ). Moreover, it is very important that our used concentrations of CORM-2 in our model in vitro are consistent with other studies [ 8 , 11 , 14 , 25 , 29 ], i.e. Tsai et al [ 8 ] observed that 50 μM CORM-2 has antioxidant activity.…”

“…Moreover, it is very important that our used concentrations of CORM-2 in our model in vitro are consistent with other studies [ 8 , 11 , 14 , 25 , 29 ], i.e. Tsai et al [ 8 ] observed that 50 μM CORM-2 has antioxidant activity. Results of Srisook et al [ 29 ] have also demonstrated that 50 μM CORM-2 inhibits the production of superoxide anion (O 2 -· ) and nitric oxide (NO · ) in macrophages stimulated by bacterial lipopolysaccharide (LPS) in vitro .…”

“…CO is also produced as a result of photooxidation, metabolism of xenobiotics and lipid peroxidation [ 2 – 5 ]. Nowadays, CO is becoming an important and versatile physiological mediator that has a beneficial effect on many models of vascular and inflammatory diseases [ 6 – 8 ]. CO regulates blood pressure and inhibits blood platelet aggregation [ 9 – 11 ].…”

Carbon monoxide-releasing molecule-3 protects against ischemic stroke by suppressing neuroinflammation and alleviating blood-brain barrier disruption

“…Carbon monoxide-releasing molecules (CORMs), a group of compounds capable of carrying and liberating controlled quantities of CO, have shown promise for delivering exogenous CO without altering COHb to toxic levels [ 11 , 18 – 20 ]. Although the mechanisms by which CORM-derived CO might offer its beneficial effects have not yet been thoroughly investigated, many studies substantiate the protective role of CORM-derived CO against cellular and tissue damage in numerous models of injury, such as renal ischemia-reperfusion injury, hemorrhagic stroke, traumatic brain injury, transplantation, sepsis, hypertension, and cardiovascular disorders [ 21 – 28 ].…”