Punicalagin Attenuates Disturbed Flow-Induced Vascular Dysfunction by Inhibiting Force-Specific Activation of Smad1/5

Abstract

BackgroundPathophysiological vascular remodeling in response to disturbed flow with low and oscillatory shear stress (OSS) plays important roles in atherosclerosis progression. Pomegranate extraction (PE) was reported having anti-atherogenic effects. However, whether it can exert a beneficial effect against disturbed flow-induced pathophysiological vascular remodeling to inhibit atherosclerosis remains unclear. The present study aims at investigating the anti-atherogenic effects of pomegranate peel polyphenols (PPP) extraction and its purified compound punicalagin (PU), as well as their protective effects on disturbed flow-induced vascular dysfunction and their underlying molecular mechanisms.MethodsThe anti-atherogenic effects of PPP/PU were examined on low-density lipoprotein receptor knockout mice fed with a high fat diet. The vaso-protective effects of PPP/PU were examined in rat aortas using myograph assay. A combination of in vivo experiments on rats and in vitro flow system with human endothelial cells (ECs) was used to investigate the pharmacological actions of PPP/PU on EC dysfunction induced by disturbed flow. In addition, the effects of PPP/PU on vascular smooth muscle cell (VSMC) dysfunction were also examined.ResultsPU is the effective component in PPP against atherosclerosis. PPP/PU evoked endothelium-dependent relaxation in rat aortas. PPP/PU inhibited the activation of Smad1/5 in the EC layers at post-stenotic regions of rat aortas exposed to disturbed flow with OSS. PPP/PU suppressed OSS-induced expression of cell cycle regulatory and pro-inflammatory genes in ECs. Moreover, PPP/PU inhibited inflammation-induced VSMC dysfunction.ConclusionPPP/PU protect against OSS-induced vascular remodeling through inhibiting force-specific activation of Smad1/5 in ECs and this mechanism contributes to their anti-atherogenic effects.

Utilização da Punica granatum L. na prevenção e tratamento da aterosclerose

“…Na pesquisa realizada por Anwaier et al (2021) foi observado que a ativação do receptor smads constitui-se também um importante sítio de ação em que é possível intervir por meio da hemodinâmica e assim tratar distúrbios vasculares decorrentes do fluxo instável. Além disso foi observado como o extrato da casca da romã, rica em polifenóis, especialmente punicalagina desempenha sua função antiaterogênica por intermédio da diminuição do LDL e consequentemente das células espumosas.…”

Analysis of the Molecular Mechanism of Punicalagin in the Treatment of Alzheimer’s Disease by Computer-Aided Drug Research Technology

“…Evidence shows the potential interaction of ALB in the blood with Aβ. As such, to improve AD and aging brain lesions, Pun may influence Aβ in the circulatory system by activating ALB . A cohort study demonstrated that brain AKT phosphorylation (pT 308 AKT1/total AKT1) is a key node of growth factors signal transduction, for example, insulin, which is associated with AD neuropathology and cognitive dysfunction .…”

“…As such, to improve AD and aging brain lesions, Pun may influence Aβ in the circulatory system by activating ALB. 7 A cohort study demonstrated that brain AKT phosphorylation (pT 308 AKT1/total AKT1) is a key node of growth factors signal transduction, for example, insulin, which is associated with AD neuropathology and cognitive dysfunction. 8 More evidence has shown a role for the tyrosine phosphotransferase Fyn of SRC family nonreceptor kinases in the pathophysiological changes of AD.…”

Mechanisms of action of natural small-molecule drugs in cardiovascular disease

“…During this change, growth factors, vasoactive substances, and hemodynamics play important roles [77]. Punicalagin, a natural small molecule, prevents vascular remodeling by inhibiting the specific activation of Smad1/5 in human ECs [59].…”