eNOS-Nitric Oxide System Contributes to a Novel Antiatherogenic Effect of Leonurine via Inflammation Inhibition and Plaque Stabilization

Abstract

Leonurine (LEO) is a bioactive small molecular compound that has protective effects on the cardiovascular system. It prevents the early progression of atherosclerosis, however, it is not clear whether LEO is effective for plaque stability. A novel mouse atherosclerosis model involving tandem stenosis (TS) of the right carotid artery combined with western diet (WD) feeding was used. ApoE-/mice were fed with a WD and received LEO administration daily for 13 weeks. TS was introduced 6 weeks after the onset of experiments. We found that LEO enhanced plaque stability by increasing fibrous cap thickness, and collagen content while decreasing the population of CD68 positive cells. Enhanced plaque stability by LEO was associated with the NOS-NO system. LEO restored the balance between eNOS and iNOS derived NO production; suppressed NF-κB signaling pathway; reduced the level of the inflammatory infiltration in plaque including cytokine IL-6 and downregulated the expression of adhesion moleculars molecules. These findings support the distinct role of LEO in plaque stabilization. In vitro studies with ox-LDL challenged HUVECs revealed that LEO balanced NO production and inhibited NF-κB/P65 nuclear translocation, thus mitigating inflammation. In conclusion, the restored balance of the NOS-NO syestem and mitigated inflammation contribute to the plaque stabilizing effect of LEO.

Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis

“…Nitric oxide is a key signaling molecule in endothelium to act as vasodilator factor, generated by nitric oxide synthase (NOS) ( 78 ). Endothelial production of NO can inhibit multiple events during AS, such as inhibiting ECs activation, macrophage infiltration ( 79 ), foam cell formation/migration ( 80 ), platelet aggregation ( 81 ), inflammation ( 82 ), thrombosis ( 83 ), vascular wall remodeling ( 84 ), and mediating vasodilation ( 85 ). The mechanism of Hcy disturbance of NO synthesis is relatively complex, asymmetric dimethylarginine (ADMA) plays an important role in it, which is an endogenous inhibitor of NOS.…”

The tandem stenosis mouse model: Towards understanding, imaging, and preventing atherosclerotic plaque instability and rupture

“…In addition to specific immunomodulatory approaches, derivatives of traditional medicines have also been explored in the TS model. The active alkaloid leonurine, an extract from the traditional Chinese medicine Herba leonuri, has been demonstrated to have protective effects in models of CVD (Ning et al, 2020). Using the TS model, Ning et al demonstrated that leonurine treatment increased plaque stability and observed increased collagen content and fibrous cap thickness and decreased inflammation.…”

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“…[48] SCM198 [4-guanidino-n-butyl syringate, Figure 3B] is a chemically synthesized compound that exhibits cardioprotective effects in myocardial infarction models [49] as well as neuroprotective effects on middle cerebral artery occluded rats. [50] Pretreatment with SCM198 (0.1, 1, and 10 mM) significantly increased SOD activity, ameliorated intracellular ROS generation, prevented the dissipation of mitochondrial membrane potential, decreased apoptotic cell death, downregulated Bax, and upregulated Bcl-2 mRNA and protein levels compared with those in 6-OHDA damaged cells. Intragastric administration of SCM198 at 18 or 60 mg/kg/day for 4 weeks significantly ameliorated apomorphine-induced contralateral rotations in 6-OHDA-lesioned rats.…”