Renal expression of constitutive NOS and DDAH: separate effects of salt intake and angiotensin.
Tojo A,Kimoto M,Wilcox C S
Kidney international
BACKGROUND:Nitric oxide (NO) is generated from NO synthase (NOS) isoforms. These enzymes can be inhibited by asymmetric dimethylarginine, which is inactivated by N(G)-N(G)-dimethylarginine dimethylaminohydrolase (DDAH). The neuroneal (nNOS) type I and endothelial (eNOS) type III constitutive NOS isoforms are expressed predominantly in the macula densa and microvascular endothelium of the renal cortex, respectively. DDAH is expressed at sites of NOS expression. Since NO may coordinate the renal responses to angiotensin II (Ang II) and changes in salt intake, we tested the hypothesis that salt intake regulates the expression of nNOS, eNOS and DDAH by Ang II acting on type 1 (AT(1)) receptors. METHODS:Groups (N = 6) of rats were adapted to low-salt (LS) or high-salt (HS) intakes for 10 days. Other groups of LS and HS rats received the AT(1) receptor antagonist losartan for six days (to test the effects of salt independent of AT(1) receptors). A further group of HS rats received an infusion of Ang II for six days (to test the effect of Ang II independent of salt intake). RESULTS:Compared with HS rats, there was a significant (P < 0.05) increase in LS rats of nNOS protein in kidney and immunohistochemical expression in the macula densa, and of eNOS protein expression and immunohistochemical expression in the microvascular endothelium, and of DDAH protein expression. Losartan prevented these effects of salt on the expression of eNOS or DDAH, both of which were also increased by Ang II infusions in HS rats. In contrast, losartan did not prevent the effects of salt on nNOS expression, which was unresponsive to Ang II infusion. The generation of NO(2)(-) released by slices of renal cortex, in the presence of saturating concentrations of L-arginine, was increased by LS, compared to HS, independent of losartan and by Ang II during HS. CONCLUSION:The expressions of eNOS in cortical microvascular endothelium and DDAH in kidney are enhanced by Ang II acting on AT(1) receptors. The expression of nNOS in the macula densa is enhanced by salt restriction independent of Ang II or AT(1) receptors.
10.1111/j.1523-1755.2000.00380.x
Endothelial p110γPI3K Mediates Endothelial Regeneration and Vascular Repair After Inflammatory Vascular Injury.
Huang Xiaojia,Dai Zhiyu,Cai Lei,Sun Kai,Cho Jaehyung,Albertine Kurt H,Malik Asrar B,Schraufnagel Dean E,Zhao You-Yang
Circulation
BACKGROUND:The integrity of endothelial monolayer is a sine qua non for vascular homeostasis and maintenance of tissue-fluid balance. However, little is known about the signaling pathways regulating regeneration of the endothelial barrier after inflammatory vascular injury. METHODS AND RESULTS:Using genetic and pharmacological approaches, we demonstrated that endothelial regeneration selectively requires activation of p110γPI3K signaling, which thereby mediates the expression of the endothelial reparative transcription factor Forkhead box M1 (FoxM1). We observed that FoxM1 induction in the pulmonary vasculature was inhibited in mice treated with a p110γ-selective inhibitor and in Pik3cg(-/-) mice after lipopolysaccharide challenge. Pik3cg(-/-) mice exhibited persistent lung inflammation induced by sepsis and sustained increase in vascular permeability. Restoration of expression of either p110γ or FoxM1 in pulmonary endothelial cells of Pik3cg(-/-) mice restored endothelial regeneration and normalized the defective vascular repair program. We also observed diminished expression of p110γ in pulmonary vascular endothelial cells of patients with acute respiratory distress syndrome, suggesting that impaired p110γ-FoxM1 vascular repair signaling pathway is a critical factor in persistent leaky lung microvessels and edema formation in the disease. CONCLUSIONS:We identify p110γ as the critical mediator of endothelial regeneration and vascular repair after sepsis-induced inflammatory injury. Thus, activation of p110γ-FoxM1 endothelial regeneration may represent a novel strategy for the treatment of inflammatory vascular diseases.
10.1161/CIRCULATIONAHA.115.020918
Common Injuries and Repair Mechanisms in the Endothelial Lining.
Meng Ling-Bing,Chen Kun,Zhang Yuan-Meng,Gong Tao
Chinese medical journal
OBJECTIVE:Endothelial cells (ECs) are important metabolic and endocrinal organs which play a significant role in regulating vascular function. Vascular ECs, located between the blood and vascular tissues, can not only complete the metabolism of blood and interstitial fluid but also synthesize and secrete a variety of biologically active substances to maintain vascular tension and keep a normal flow of blood and long-term patency. Therefore, this article presents a systematic review of common injuries and healing mechanisms for the vascular endothelium. DATA SOURCES:An extensive search in the PubMed database was undertaken, focusing on research published after 2003 with keywords including endothelium, vascular, wounds and injuries, and wound healing. STUDY SELECTION:Several types of articles, including original studies and literature reviews, were identified and reviewed to summarize common injury and repair processes of the endothelial lining. RESULTS:Endothelial injury is closely related to the development of multiple cardiovascular and cerebrovascular diseases. However, the mechanism of vascular endothelial injury is not fully understood. Numerous studies have shown that the mechanisms of EC injury mainly involve inflammatory reactions, physical stimulation, chemical poisons, concurrency of related diseases, and molecular changes. Endothelial progenitor cells play an important role during the process of endothelial repair after such injuries. What's more, a variety of restorative cells, changes in cytokines and molecules, chemical drugs, certain RNAs, regulation of blood pressure, and physical fitness training protect the endothelial lining by reducing the inducing factors, inhibiting inflammation and oxidative stress reactions, and delaying endothelial caducity. CONCLUSIONS:ECs are always in the process of being damaged. Several therapeutic targets and drugs were seeked to protect the endothelium and promote repair.
10.4103/0366-6999.241805
How Structure, Mechanics, and Function of the Vasculature Contribute to Blood Pressure Elevation in Hypertension.
Schiffrin Ernesto L
The Canadian journal of cardiology
Large conduit arteries and the microcirculation participate in the mechanisms of elevation of blood pressure (BP). Large vessels play roles predominantly in older subjects, with stiffening progressing after middle age leading to increases in systolic BP found in most humans with aging. Systolic BP elevation and increased pulsatility penetrate deeper into the distal vasculature, leading to microcirculatory injury, remodelling, and associated endothelial dysfunction. The result is target organ damage in the heart, brain, and kidney. In younger individuals genetically predisposed to high BP, increased salt intake or other exogenous or endogenous risk factors for hypertension, including overweight and excess alcohol intake, lead to enhanced sympathetic activity and vasoconstriction. Enhanced vasoconstrictor responses and myogenic tone become persistent when embedded in an increased extracellular matrix, resulting in remodelling of resistance arteries with a narrowed lumen and increased media-lumen ratio. Stimulation of the renin-angiotensin-aldosterone and endothelin systems and inflammatory and immune activation, to which gut microbiome dysbiosis may contribute as a result of salt intake, also participate in the injury and remodelling of the microcirculation and endothelial dysfunction. Inflammation of perivascular fat and loss of anticontractile factors play roles as well in microvessel remodelling. Exaggerated myogenic tone leads to closure of terminal arterioles, collapse of capillaries and venules, functional rarefaction, and eventually to anatomic rarefaction, compromising tissue perfusion. The remodelling of the microcirculation raises resistance to flow, and accordingly raises BP in a feedback process that over years results in stiffening of conduit arteries and systo-diastolic or predominantly systolic hypertension and, more rarely, predominantly diastolic hypertension. Thus, at different stages of life and the evolution of hypertension, large vessels and the microcirculation interact to contribute to BP elevation.
10.1016/j.cjca.2020.02.003
Apoptosis signal-regulating kinase 1 deficiency eliminates cardiovascular injuries induced by high-salt diet.
Kataoka Keiichiro,Tokutomi Yoshiko,Yamamoto Eiichiro,Nakamura Taishi,Fukuda Masaya,Dong Yi-Fei,Ichijo Hidenori,Ogawa Hisao,Kim-Mitsuyama Shokei
Journal of hypertension
OBJECTIVES:High-salt diet is closely associated with the increase in cardiovascular events. However, the mechanism of high-salt-induced cardiovascular injury is unknown. The present study was undertaken to test our hypothesis that apoptosis signal-regulating kinase (ASK) 1 may be involved in salt-induced cardiovascular injury. METHODS:Wild-type and ASK1-/- mice were fed a low-salt or a high-salt diet for 10 weeks and the effects of high-salt diet on food intake, urinary volume and electrolyte excretion, and cardiovascular injury were compared between both groups of mice. RESULTS:High-salt diet in wild-type and ASK1-/- mice similarly increased food intake, water intake, urine volume, and urinary sodium excretion, and comparably decreased plasma renin activity and aldosterone. Thus, ASK1 appears to play a minor role in the increase in natriuresis and the decrease in plasma renin, and aldosterone caused by high-salt diet. High-salt diet enhanced the phosphorylation of cardiovascular ASK1 in wild-type mice. High-salt diet in wild-type mice enhanced cardiac transforming growth factor-β1, interstitial fibrosis, coronary perivascular fibrosis, and inflammatory cell infiltration, and these changes were associated with the increase in cardiac superoxide and Nox2. ASK1 deficiency abolished the above-mentioned high-salt-induced cardiac injury. High-salt diet also caused the impairment of vascular endothelium-dependent relaxation by acetylcholine and increased vascular superoxide, and Nox2 in wild-type mice, whereas it did not cause vascular injury in ASK1-/- mice. CONCLUSION:ASK1 is implicated in cardiac inflammation and fibrosis, and vascular endothelial dysfunction caused by high-salt diet, through the enhancement of oxidative stress.
10.1097/HJH.0b013e32833fc8b0
Inflammasome-Independent NALP3 Contributes to High-Salt Induced Endothelial Dysfunction.
Fu Hui,Chen Ji-Kuai,Lu Wen-Jie,Jiang Yu-Jie,Wang Yuan-Yuan,Li Dong-Jie,Shen Fu-Ming
Frontiers in pharmacology
Na is an important nutrient and its intake, mainly from salt (NaCl), is essential for normal physiological function. However, high salt intake may lead to vascular injury, independent of a rise in blood pressure (BP). Canonical NALP3 inflammasome activation is a caspase-1 medicated process, resulting in the secretion of IL-18 and IL-1β which lead to endothelial dysfunction. However, some researches uncovered a direct and inflammasome-independent role of NALP3 in renal injury. Thus, this study was designed to investigate the possible mechanisms of NALP3 in high salt induced endothelial dysfunction. Changes in endothelial function were measured by investigating mice (C57BL/6J, NALP3 and wild-type, WT) fed with normal salt diet (NSD) or high salt diet (HSD) for 12W, and thoracic aortic rings from C57BL/6J mice cultured in high-salt medium. Changes of tube formation ability, intracellular reactive oxygen species (ROS), and NALP3 inflammasome expression were detected using mouse aortic endothelial cells (MAECs) cultured in high-salt medium. Consumption of HSD for 12W did not affect BP or body weight in C57BL/6J mice. Endothelium-dependent relaxation (EDR) decreased significantly in C57BL/6J mice fed with HSD for 12W, and in isolated thoracic aortic rings cultured in high-salt medium for 24 h. Results from the aortic ring assay also revealed that the angiogenic function of thoracic aortas was impaired by either consumption of HSD or exposure to high-salt medium. NALP3 mice fed with HSD showed a relatively mild decrease in EDR function when compared with WT mice. Tube length of thoracic aortic rings from NALP3 mice was longer than those from WT mice after receiving high-salt treatment. Inhibiting NALP3 with a NALP3 antagonist, small interfering (si) RNA experiments using si-NALP3, and decomposing ROS significantly improved tube formation ability in MAECs under high salt medium. NALP3 expression was increased in MAECs cultured with high salt treatment and inhibiting NALP3 reversed the down-regulation of p-eNOS induced by high salt in MAECs. High salt intake impairs endothelial function, which is at least in part mediated by increasing NALP3 expression.
10.3389/fphar.2018.00968
Transient Receptor Potential Melastatin 4 (TRPM4) Contributes to High Salt Diet-Mediated Early-Stage Endothelial Injury.
Ding Xiao-Qing,Ban Tao,Liu Zeng-Yan,Lou Jie,Tang Liang-Liang,Wang Jia-Xin,Chu Wen-Feng,Zhao Dan,Song Bin-Lin,Zhang Zhi-Ren
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
BACKGROUND/AIMS:The present study investigated whether the transient receptor potential melastatin 4 (TRPM4) channel plays a role in high salt diet (HSD)-induced endothelial injuries. METHODS:Western blotting and immunofluorescence were used to examine TRPM4 expression in the mesenteric endothelium of Dahl salt-sensitive (SS) rats fed a HSD. The MTT, TUNEL, and transwell assays were used to evaluate the cell viability, cell apoptosis, and cell migration, respectively, of human umbilical vein endothelial cells (HUVECs). Enzyme-linked immunosorbent assays were used to determine the concentrations of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion protein 1 (VCAM-1), and E-selectin. Carboxy-H2DCFDA, a membrane-permeable reactive oxygen species (ROS)-sensitive fluorescent probe, was used to detect intracellular ROS levels. RESULTS:TRPM4 was mainly expressed near the plasma membrane of mesenteric artery endothelial cells, and its expression level increased in SS hypertensive rats fed a HSD. Its protein expression was significantly upregulated upon treatment with exogenous hydrogen peroxide (H2O2) and aldosterone in cultured HUVECs. Cell viability decreased upon treatment with both agents in a concentration-dependent manner, which could be partially reversed by 9-phenanthrol, a specific TRPM4 inhibitor. Exogenous H2O2 induced apoptosis, enhanced cell migration, and increased the release of adhesion molecules, including ICAM-1, VCAM-1, and E-selectin, all of which were significantly attenuated upon treatment with 9-phenanthrol. Aldosterone and H2O2 induced the accumulation of intracellular ROS, which was significantly inhibited by 9-phenanthrol, suggesting that oxidative stress is one of the mechanisms underlying aldosterone-induced endothelial injury. CONCLUSIONS:Given the fact that oxidative stress and high levels of circulating aldosterone are present in hypertensive patients, we suggest that the upregulation of TRPM4 in the vascular endothelium may be involved in endothelial injuries caused by these stimuli.
10.1159/000459695
Salt Reduction to Prevent Hypertension and Cardiovascular Disease: JACC State-of-the-Art Review.
He Feng J,Tan Monique,Ma Yuan,MacGregor Graham A
Journal of the American College of Cardiology
There is strong evidence for a causal relationship between salt intake and blood pressure. Randomized trials demonstrate that salt reduction lowers blood pressure in both individuals who are hypertensive and those who are normotensive, additively to antihypertensive treatments. Methodologically robust studies with accurate salt intake assessment have shown that a lower salt intake is associated with a reduced risk of cardiovascular disease, all-cause mortality, and other conditions, such as kidney disease, stomach cancer, and osteoporosis. Multiple complex and interconnected physiological mechanisms are implicated, including fluid homeostasis, hormonal and inflammatory mechanisms, as well as more novel pathways such as the immune response and the gut microbiome. High salt intake is a top dietary risk factor. Salt reduction programs are cost-effective and should be implemented or accelerated in all countries. This review provides an update on the evidence relating salt to health, with a particular focus on blood pressure and cardiovascular disease, as well as the potential mechanisms.
10.1016/j.jacc.2019.11.055
Salt reduction to prevent hypertension: the reasons of the controversy.
He Feng J,Campbell Norm R C,Woodward Mark,MacGregor Graham A
European heart journal
There is a causal relationship between dietary salt intake and blood pressure. A reduction in salt intake from the current world average of ∼10 g/day to the WHO recommended level of <5 g/day, lowers blood pressure and reduces the risk of cardiovascular disease and all-cause mortality. However, a few cohort studies have claimed that there is a J-shaped relationship between salt intake and cardiovascular risk, i.e. both high and low salt intakes are associated with an increased risk. These cohort studies have several methodological problems, including reverse causality, and inaccurate and biased estimation of salt intake, e.g. from a single spot urine sample with formulas. Recent studies have shown that the formulas used to estimate salt intake from spot urine cause a spurious J-curve. Research with inappropriate methodology should not be used to refute the robust evidence on the enormous benefits of population-wide reduction in salt intake. Several countries, e.g. Finland, the UK, have successfully reduced salt intake, which has resulted in falls in population blood pressure and deaths from stroke and ischaemic heart disease. Every country should develop and implement a coherent, workable strategy to reduce salt intake. Even a modest reduction in salt intake across the whole population will lead to a major improvement in public health, along with huge cost-savings to the healthcare service.
10.1093/eurheartj/ehab274