In arterial media, VSMC is at low proliferative indices (<0.05%) and remains in the G0/G1 phase of the cell cycle.
Hence, MMPs and their regulatory signaling have been considered as promising targets for anti-atherosclerotic agents. One review study concluded that oxidative stress could enhance MMP activity and expression, and recent studies further indicate that MMP-mediated ECM remodeling is modulated by reactive oxygen species (ROS).
Animal crossing new leaf hibiscus Activator#
Moreover, the gene expression of MMPs is majorly regulated by the transcriptional factors, such as activator protein-1 (AP-1) or nuclear factor-kappaB (NF-κB) through the serine/threonine protein kinase PKB (also known as Akt) or extracellular signal-regulated kinase (ERK) pathways, or by the MMP protein activators or inhibitors. Among them, the gelatinases (MMP-2 and MMP-9) degrade efficiently native collagen types IV and laminin, and promote a VSMC migratory phenotype. MMPs are a subfamily of the metzincin superfamily of endogenous proteinases that break down components of ECM. Identification of key proteins involved in the process, such as matrix metalloproteinases (MMPs), is vital for understanding atherosclerosis and devising new therapies. In the atherosclerotic process, VSMC migrates from the media to the intima, forms the neointima progressively with abundant levels of extracellular matrix (ECM) proteins, and then eventually leads to plaque formation. VSMC is normally quiescent, but upon vascular injury, it transforms into a more synthetic phenotype with progressively increasing capacity for activation, proliferation, and migration. Thus, inhibition of abnormal VSMC migration and proliferation is an attractive strategy for clinical therapy of atherosclerosis and restenosis after percutaneous coronary interventions. Subsequently, VSMC transforms and proliferates into foam cells, and thus the accumulation of foam cells leading to fatty streaks results in the formation of atherosclerotic plaques. In the lesion progression, these activated macrophages still secrete proinflammatory cytokines, especially tumor necrosis factor-alpha (TNF-α), which enhances VSMC migration and proliferation. Oxidized LDL triggers endothelial cells to release chemokines in contribution to recruitment of monocytes, resulting in the transformation of the lipid-laden macrophages into foam cells. Elevated plasma LDL concentration contributes to the initiation of atherosclerosis. Our data present the first evidence of HLPs as an inhibitor of VSMC dysfunction, and provide a new mechanism for its anti-atherosclerotic activity.Ītherosclerosis is considered a chronic inflammatory process and involves a complex pathophysiological effect, including endothelial dysfunction, low-density lipoprotein (LDL) oxidation, foam cell formation, and vascular smooth muscle cell (VSMC) proliferation and migration at different stages of this disease. In vivo, HLPs improved atherosclerotic lesions, and abnormal VSMC migration and proliferation. HLPs also attenuated reactive oxygen species (ROS) production against TNF-α stimulation. On the other hand, HLP-mediated cell cycle G0/G1 arrest might be exerted by inducing the expressions of p53 and its downstream factors that, in turn, suppress cyclin E/cdk2 activity, preventing retinoblastoma (Rb) phosphorylation and the subsequent dissociation of Rb/E2F complex. Non-cytotoxic doses of HLPs abolished the TNF-α-induced MMP-9 expression and cell migration via inhibiting the protein kinase PKB (also known as Akt)/activator protein-1 (AP-1) pathway.
Firstly, VSMC A7r5 cells pretreated with TNF-α were demonstrated to trigger abnormal proliferation and affect matrix metalloproteinase (MMP) activities. In this study, we examined the anti-atherosclerotic effect of Hibiscus leaf polyphenols (HLPs) against abnormal VSMC migration and proliferation in vitro and in vivo. Hibiscus leaf has been showed to inhibit endothelial cell oxidative injury, low-density lipoprotein oxidation, and foam cell formation.
Plant-derived polyphenols have attracted considerable attention in the prevention of atherosclerosis. The proliferation and migration of vascular smooth muscle cells (VSMCs) are major events in the development of atherosclerosis following stimulation with proinflammatory cytokines, especially tumor necrosis factor-alpha (TNF-α).