Mechanism Studies Of Plant Polyphenols Protecting Against Hypertension And Target Organ Damage Induced By High Salt

Background:Hypertension is the most common chronic diseases associated with aging, but also themost important risk factor for heart and vascular disease. Over the past century, around therelationship between salt and blood pressure, it is confirmed that salt is the important riskfactor of hypertensive. However, salt loading or salt restriction leads to a different bloodpressure response in the crowd, that is salt-sensitive. Abnormal renal physiology is animportant factor to induce and maintain high blood pressure, and high blood pressure can be acause of chronic renal damage, also, which both affect each other. Recent studies have foundthat the vascular endothelium oxidative stress involved in high blood pressure, kidney damage,the aging vascular dysfunction and a variety of cardiovascular disease development.Hypertension, especially salt-sensitive hypertension, is closely related to the pathogenesis ofendothelial dysfunction. Epidemiological studies have shown that a variety of dietary factorsaffect blood pressure and vascular function. In the past ten years, reducing sodium intake andincreaseing potassium salt intake, vegetable and fruit dietary can effectively lower bloodpressure and improve blood vessel function. The plant polyphenols widely distributed in avariety of fruits, vegetables and grains, and its impact on health attentioned by the peoplemore and more. Apigenin and curcumin are two important plant polyphenols. Previous studiesfound that apigenin and curcumin with effects of reduceing blood pressure, vasodilation,anti-oxidation, but the exact mechanisms of those are unclear. Recent studies found thatactivation of peroxisome proliferator-activated receptor δ (PPARδ) generating non-geneticeffects through phosphatidylinositol-3-kinase/serine-threonine kinase/endothelial nitric oxidesynthase (PI3K/Akt-eNOS) pathway improve endothelial function. Apigenin activatingPPARγ plays anti-inflammatory role. Studies also have shown that curcumin can adjust theaging mouse endothelial dysfunction related to5’-AMP-activated protein kinase (AMPK)signaling pathway. Therefore, we hypothesized that apigenin can activate PI3K/Akt-eNOS through PPARδ, promote the endothelial synthesis and release of nitric oxide (NO), improveblood vessel function, prevention of salt-sensitive high blood pressure and protect the kidneys.Curcumin can reduce reactive oxygen species (ROS) generation through AMPK-Uncouplingprotein2(UCP2) pathway and improve the aging cerebrovascular dysfunction.Objective:In order to verify the above assumptions, the present study was divided into three parts.First, we monitored blood pressure and vascular diastolic function of deoxycorticosteroneacetate-salt (DOCA-salt) hypertensive rats, to investigate the effect by apigenin ofanti-salt-sensitive hypertension and improving vascular function. Analysising24-hour urinaryalbumin and glomerulosclerosis of DOCA-salt hypertensive rats, to explore effect by apigeninprotecting against renal damage of salt-sensitive hypertensive. Second, comparing ROS andNO production and PPARδ-PI3K/Akt-eNOS pathway protein expression of arteries fromDOCA-salt hypertensive rats. Third, we provide in vivo and in vitro experimental evidencethat curcumin reduces ROS production and increases NO production, thereby rescuingcerebrovascular endothelium dysfunction through the AMPK/UCP2pathway in agingrodents.Materials and Methods:1. Non-invasive rat tail blood pressure, carotid artery mean arterial blood pressure ofDOCA-salt hypertensive rats.2. HE staining of kidney sections of DOCA-salt hypertensive rats.3.24-hour urine urine protein analysising of DOCA-salt hypertensive rats.4. Determination renal interlobular artery function after acute stimulation or long-terminterventions by apigenin. Cerebral basilar artery function changes by curcumin acutestimulation or long-term intervention.5. Fluorescence imaging of ROS and NO levels of DOCA-salt hypertensive rats renalartery. ROS and NO basilar arteries from aging rats after long-term curcumin intervention.6. Western blot detection of NO synthesis signaling proteins expression (PPARδ, Akt,eNOS, phospho-eNOS) in renal artery by apigenin treatment. Protein Level of ROS pathway(AMPK, UCP2) in brain basilar artery and endothelial cells treated by curcuminResults:1. Dietary apigenin reduced blood pressure, improved artery endothelium-dependent vasodilation, prevented proteinuria and glomerular sclerosis in DOCA-salt hypertensive rats.2. Dietary apigenin reduced artery ROS levels, increased NO production andphosphorylation of eNOS protein expression in DOCA-salt hypertensive rats.3. Dietary apigenin can significantly improve the DOCA-salt hypertensive rats renalartery endothelium-dependent vasodilation, and apigenin showed a concentration-dependentmanner vasodilation of rat renal artery, which dependented with PPARδ-PI3K/Akt-eNOSpathway.4. Impaired cerebrovascular endothelial function and increased ROS in aging rats can beimproved by chronic dietary curcumin through a UCP2-dependent pathway.5. Curcumin mediated UCP2up-regulation involves the activation of the AMPK in thecerebrovascular endothelium.6. Activation of the AMPK/UCP2pathway by curcumin antagonizes the production ofsuperoxide anions and prevents NO reduction in endothelial cells.Conclusions:1. Apigenin reduced salt-sensitive hypertension, improved endothelium-dependentvascular function and prevented against renal damage.2. Apigenin activated vascular PPARδ and increased NO production throughPI3K/Akt-eNOS pathway.3. Curcumin improves aging-related cerebrovascular dysfunction through theAMPK/UCP2pathway.