The protective mechanism of folic acid on hyperhomocysteinemia-related arterial injury in spontaneously hypertensive rats: Folic acid against arterial inflammation

Background Hypertension associated with hyperhomocysteinemia (HHcy) is correlated with a high risk of vascular diseases. Studies found that folic acid (FA) supplementation can reduce the risk of cardiovascular and cerebrovascular events. The aim of the present study was to explore the potential mechanisms of FA attenuating HHcy-related arterial injury in spontaneously hypertensive rats (SHRs). Methods 24 SHRs were randomized into the control group, the HHcy group, and the HHcy + FA group (8 per group). The SHRs in the HHcy group and the HHcy + FA group were given DL-Hcy intraperitoneally to mimic hypertension associated with HHcy. The SHRs in the HHcy + FA group were given FA by gavage to mimic an FA-fortified diet. The histopathology and immunohistochemistry of rat aorta and carotid artery were analyzed, and the relative expression levels of immune/inflammation and oxidative stress molecules in arterial tissue were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Results FA significantly reduced the expression levels of nuclear factor-κ-gene binding (NF-κB) p65/Rela and interleukin-6 (IL-6) in rat arterial tissues, as well as the levels of plasma HHcy and serum malondialdehyde (MDA) in hypertension associated with HHcy rats ( p < 0.05). At the same time, FA significantly increased the serum superoxide dismutase (SOD) level in hypertension associated with HHcy rats, and even the SOD level of the HHcy + FA group was higher than that of the control group ( p < 0.05). However, HHcy induced the opposite results of the above indicators in SHRs compared with the control group ( p < 0.05). Conclusions The arterial protection mechanisms of FA are related to reducing the concentration of HHcy to eliminate the tissue toxicity of HHcy, inhibiting NF-κBp65/Rela/IL-6 pathway molecules to regulate inflammatory response, and promoting the potential anti-oxidative stress pathway molecules to reduce oxidative stress level.

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Folic Acid Can Reduce Hyperhomocysteinemia-induced Vascular Damage by Immune/Inflammatory Response in Spontaneously Hypertensive Rats

10.21203/rs.3.rs-25948/v1 ◽

2020 ◽

Author(s):

Lihua Zhang ◽

Zhongliang li ◽

Changcheng Xing ◽

Ning Gao ◽

Ping Cao ◽

...

Keyword(s):

Oxidative Stress ◽

Folic Acid ◽

Spontaneously Hypertensive Rats ◽

Vascular Damage ◽

Inflammatory Factors ◽

Hypertensive Rats ◽

Stress Indicators ◽

Spontaneously Hypertensive ◽

Inflammatory Molecules ◽

Oxidative Stress Indicators

Abstract Background Hypertension associated with hyperhomocysteinemia (HHcy) is correlated with a high risk of vascular diseases. However, the mechanisms of HHcy-associated hypertensive vascular damage and the efficacy of folic acid (FA) as a treatment have not been fully elucidated. The aim of the present study was to evaluate the role of immune/inflammatory molecules and oxidizing factors in HHcy-associated hypertensive vascular damage, and to observe the intervention effect of FA on the two vascular injury factors. Methods Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) were administered DL-Hcy intraperitoneally to mimic HHcy and hypertension associated with HHcy for 12 weeks. WKYs and SHRs were randomized into WKY group, HHcy group, SHR group, SHR + HHcy group and SHR + HHcy + FA group. Mean tail artery blood pressure, plasma Hcy, serum SOD and MDA of rats in each group were compared. The thoracic aorta and bilateral carotid artery of rats were harvested for morphometric and immunostaining analyses. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to detect the expression of immune/inflammatory molecules such as TNF-α, IL-6, NF-κB p65/Rela and NF-κB2 and oxidative factors such as Nox2 and Nox4. Results We found that vascular inflammatory factors of vascular adhesion protein-1 (VAP-1), interleukin-6 (IL-6), and nuclear factor-κ-gene binding (NF-κB) p65/Rela in HHcy-associated hypertensive rats were significantly higher than those in SHRs (P༜0.05). While the oxidative stress indicators of Nox2 and Nox4 in HHcy-associated hypertensive rats were not significantly higher than those in SHRs (P༞0.05). Compared with SHRs, FA intervention in HHcy-associated hypertensive rats significantly increased serum superoxide dismutase (SOD) levels (P = 0.000) and significantly reduced vascular inflammatory factors of IL-6 and NF-κB p65/Rela (P༜0.05), but did not significantly change the oxidative stress indicators of Nox2 and Nox4 (P༞0.05). Conclusions HHcy-induced immune/inflammatory response plays a dominant role in vascular damage of HHcy-associated hypertensive rats. In addition to reducing the negative effects of HHcy, FA might involve unique antioxidant effects and inhibition of immune/inflammatory overreaction for HHcy-associated hypertensive rats.

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1638: Erectile Dysfunction and Oxidative Stress-Media Ted Cavernosal Cell Death in Spontaneously Hypertensive Rats

The Journal of Urology ◽

10.1016/s0022-5347(18)38846-3 ◽

2004 ◽

Vol 171 (4S) ◽

pp. 433-433

Author(s):

Steven Kuntz ◽

Steven White ◽

Michael Alba ◽

Mahadevan Rajasekaran

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Erectile Dysfunction ◽

Spontaneously Hypertensive Rats ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

And Oxidative Stress

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In Vivo Evidence for Microvascular Oxidative Stress in Spontaneously Hypertensive Rats

Hypertension ◽

10.1161/01.hyp.25.5.1083 ◽

1995 ◽

Vol 25 (5) ◽

pp. 1083-1089 ◽

Cited By ~ 203

Author(s):

Hidekazu Suzuki ◽

Allen Swei ◽

Benjamin W. Zweifach ◽

Geert W. Schmid-Schönbein

Keyword(s):

Oxidative Stress ◽

Spontaneously Hypertensive Rats ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

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Pomegranate extract decreases oxidative stress and alleviates mitochondrial impairment by activating AMPK-Nrf2 in hypothalamic paraventricular nucleus of spontaneously hypertensive rats

Scientific Reports ◽

10.1038/srep34246 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 21

Author(s):

Wenyan Sun ◽

Chunhong Yan ◽

Bess Frost ◽

Xin Wang ◽

Chen Hou ◽

...

Keyword(s):

Oxidative Stress ◽

Paraventricular Nucleus ◽

Spontaneously Hypertensive Rats ◽

Hypothalamic Paraventricular Nucleus ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Mitochondrial Impairment

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Polyphenol-containing azuki bean (Vigna angularis) seed coats attenuate vascular oxidative stress and inflammation in spontaneously hypertensive rats

The Journal of Nutritional Biochemistry ◽

10.1016/j.jnutbio.2009.11.004 ◽

2011 ◽

Vol 22 (1) ◽

pp. 16-21 ◽

Cited By ~ 50

Author(s):

Yuuka Mukai ◽

Shin Sato

Keyword(s):

Oxidative Stress ◽

Spontaneously Hypertensive Rats ◽

Azuki Bean ◽

Vigna Angularis ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Vascular Oxidative Stress ◽

Seed Coats

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Immunohistochemical Analysis of 4-HNE, NGAL, and HO-1 Tissue Expression after Apocynin Treatment and HBO Preconditioning in Postischemic Acute Kidney Injury Induced in Spontaneously Hypertensive Rats

Antioxidants ◽

10.3390/antiox10081163 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1163

Author(s):

Sanjin Kovacevic ◽

Milan Ivanov ◽

Maja Zivotic ◽

Predrag Brkic ◽

Zoran Miloradovic ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Spontaneously Hypertensive Rats ◽

Kidney Injury ◽

Immunohistochemical Analysis ◽

Tissue Expression ◽

Pure Oxygen ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Renal Expression

Oxidative stress has been considered as a central aggravating factor in the development of postischemic acute kidney injury (AKI). The aim of this study was to perform the immunohistochemical analysis of 4-hydroxynonenal (4-HNE), neutrophil gelatinase-associated lipocalin (NGAL), and heme oxygenase-1 (HO-1) tissue expression after apocynin (APO) treatment and hyperbaric oxygenation (HBO) preconditioning, applied as single or combined protocol, in postischemic acute kidney injury induced in spontaneously hypertensive rats (SHR). Twenty-four hours before AKI induction, HBO preconditioning was carried out by exposing to pure oxygen (2.026 bar) twice a day, for 60 min in two consecutive days. Acute kidney injury was induced by removal of the right kidney while the left renal artery was occluded for 45 min by atraumatic clamp. Apocynin was applied in a dose of 40 mg/kg body weight, intravenously, 5 min before reperfusion. We showed increased 4-HNE renal expression in postischemic AKI compared to Sham-operated (SHAM) group. Apocynin treatment, with or without HBO preconditioning, improved creatinine and phosphate clearances, in postischemic AKI. This improvement in renal function was accompanied with decreased 4-HNE, while HO-1 kidney expression restored close to the control group level. NGAL renal expression was also decreased after apocynin treatment, and HBO preconditioning, with or without APO treatment. Considering our results, we can say that 4-HNE tissue expression can be used as a marker of oxidative stress in postischemic AKI. On the other hand, apocynin treatment and HBO preconditioning reduced oxidative damage, and this protective effect might be expected even in experimental hypertensive condition.

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Abstract 309: Role of Hemeoxygenase in the Reno-Protective Effects of Soluble Epoxide Hydrolase Inhibition In Diabetic Spontaneously Hypertensive Rats

Hypertension ◽

10.1161/hyp.60.suppl_1.a309 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Ahmed A Elmarakby ◽

Jessica Faulkner ◽

Chelsey Pye ◽

Babak Baban ◽

Katelyn Rouch ◽

...

Keyword(s):

Protective Effect ◽

Renal Injury ◽

Renal Fibrosis ◽

Spontaneously Hypertensive Rats ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Control Group ◽

Protective Effects ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

We previously showed that inhibition of soluble epoxide hydrolase (sEH) increased epoxyeicosatrienoic acids (EETs) levels and reduced renal injury in diabetic mice and these changes were associated with induction of hemeoxygenase-1 (HO-1). The present study determines whether the inhibition of HO negates the reno-protective effect of sEH inhibition in diabetic spontaneously hypertensive rats as a model of diabetic nephropathy in which hypertension coexists with diabetes. After six weeks of induction of diabetes with streptozotocin, SHR were divided into the following groups: untreated, treated with the sEH inhibitor, trans -4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (AUCB), treated with the HO inhibitor, stannous mesoporphyrin (SnMP), and treated with both inhibitors for four more weeks; non diabetic SHR served as a control group. Although inhibition of sEH increased renal EETs/DHETEs ratio and HO-1 activity in diabetic SHR, it did not significantly alter blood pressure (plasma EETs/DHETEs ratio was 0.5± 0.1 in AUCB-treated vs. 0.1± 0.01 in untreated diabetic SHR, P<0.05). Treatment of diabetic SHR with AUCB reduced the elevation in urinary albumin and nephrin excretion (albuminuria was 6.5± 0.5 in AUCB-treated diabetic SHR vs. 9± 1.7 mg/day in untreated diabetic SHR and nephrinuria was 70±11 in AUCB-treated diabetic SHR vs. 111± 9 μg/day in untreated diabetic SHR, P<0.05) whereas co-administration of SnMP with AUCB prevented these changes (albuminuria was 10.6± 0.6 mg/day and nephrinuria was 91±11 μg/day). Immunohistochemical analysis revealed elevations in renal fibrosis and apoptosis as evidenced by increased renal TGF-β, fibronectin and annexin V expression in diabetic SHR and these changes were reduced with sEH inhibition. Co-administration of SnMP with AUCB prevented its ability to reduce renal fibrosis and apoptosis in diabetic SHR. In addition, SnMP treatment also prevented AUCB-induced decreases in renal macrophage infiltration and renal TGF-β, NFκB and MCP-1 levels in diabetic SHR. These data suggest that HO-1 induction is involved in the protective effect of sEH inhibition against diabetic renal injury.

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Changes of Blood Pressure Rhythm and Clock Protein Expression Levels in Spontaneously Hypertensive Rats After Ischemia-Reperfusion

10.21203/rs.3.rs-161485/v1 ◽

2021 ◽

Author(s):

Jing Jin ◽

Yumeng Liu ◽

Jing Huang ◽

Dong Zhang ◽

Jian Ge ◽

...

Keyword(s):

Blood Pressure ◽

Protein Expression ◽

Circadian Clock ◽

Spontaneously Hypertensive Rats ◽

Ischemia Reperfusion ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Expression Levels ◽

The Relationship ◽

Clock Protein

Abstract Objective A variety of circadian patterns of blood pressure after ischemic stroke in patients with essential hypertension appear to be a potential risk of stroke recurrence, but the mechanism is still unclear. This study intends to reveal the changes in blood pressure rhythm and circadian clock protein expression levels in spontaneously hypertensive rats (SHR) after ischemia-reperfusion, and the relationship between the two. Methods Using the SHR middle cerebral artery occlusion experimental model, the systolic blood pressure was continuously monitored for 24 hours after the operation to observe the blood pressure rhythm. The rat tail vein blood was taken every 3h, and the serum CLOCK, BMAL1, PER1 and CRY1 protein expression levels were detected by Elisa. Pearson correlation analysis counted the relationship between SHR blood pressure rhythm and circadian clock protein fluctuation after ischemia-reperfusion. Results The proportion of abnormal blood pressure patterns in the SHR + tMCAO group was significantly higher than that in the SHR group, the serum CLOCK expression was relatively constant, and the circadian rhythm of BMAL1, PER1 and CRY1 protein expression changed significantly. Pearson analysis showed that PER1 protein level was negatively correlated with dipper (r = -0.565, P = 0.002) and extreme-dipper (r = -0.531, P = 0.001) blood pressure, and was significantly positively correlated with non-dipper blood pressure (r = 0.620, P < 0.001). Conclusion The rhythm pattern of blood pressure after ischemia-reperfusion in SHR is obviously disordered, and it is closely related to the regulation of Per1 gene.

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Combination of Exercise Training and SOD Mimetic Tempol Enhances Upregulation of Nitric Oxide Synthase in the Kidney of Spontaneously Hypertensive Rats

International Journal of Hypertension ◽

10.1155/2020/2142740 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Pengyu Cao ◽

Osamu Ito ◽

Daisuke Ito ◽

Rong Rong ◽

Yang Zheng ◽

...

Keyword(s):

Nitric Oxide ◽

Exercise Training ◽

Nadph Oxidase ◽

Oxidase Activity ◽

Spontaneously Hypertensive Rats ◽

Hypertensive Rats ◽

Sod Activity ◽

Spontaneously Hypertensive ◽

Nadph Oxidase Activity ◽

Expression Levels

Both exercise training (Ex) and superoxide dismutase (SOD) mimetic tempol have antihypertensive and renal protective effects in rodent models of several hypertensions. We recently reported that Ex increases nitric oxide (NO) production and the expression levels of endothelial and neuronal NO synthase (eNOS and nNOS) in the kidney and aorta of the spontaneously hypertensive rats (SHR) and normotensive Wistar–Kyoto rats (WKY). We also found that endogenous hydrogen peroxide (H2O2) upregulates the expression levels of eNOS and nNOS in SHR. To elucidate the mechanism of the Ex-upregulated NO system in the kidney, we examined the additive effect of Ex and tempol on the renal NO system in SHR and WKY. Our data showed that, in SHR, both Ex and tempol increase the levels of H2O2 and nitrate/nitrite (NOx) in plasma and urine. We also observed an increased renal NOS activity and upregulated expression levels of eNOS and nNOS with decreased NADPH oxidase activity. The effects of the combination of Ex and tempol on these variables were cumulate in SHR. On the other hand, we found that Ex increases these variables with increased renal NADPH oxidase activity, but tempol did not change these variables or affect the Ex-induced upregulation in the activity and expression of NOS in WKY. The SOD activity in the kidney and aorta was activated by tempol only in SHR, but not in WKY; whereas Ex increased SOD activity only in the aorta in both SHR and WKY. These results indicate that Ex-induced endogenous H2O2 produced in the blood vessel and other organs outside of the kidney may be carried to the kidney by blood flow and stimulates the NO system in the kidney.

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