The protective mechanism of folic acid on hyperhomocysteinemia-related arterial injury in spontaneously hypertensive rats: Folic acid against arterial inflammation
Restricted accessResearch articleFirst published online October, 2022
The protective mechanism of folic acid on hyperhomocysteinemia-related arterial injury in spontaneously hypertensive rats: Folic acid against arterial inflammation
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.
HuDYXuXP. Prevention of stroke relies on valid control “H” type hypertension. Chin J Intern Med2009; 47: 976–977.
2.
Jian-PingLIHuoYLiuP, et al.Efficacy and safety of Enalapril-Folate acid tablets in lowering blood pressure and plasma homocysteine. J Peking Univ (2007); 17: 614–618.
3.
ChanSHHungCHShihJY, et al.Exercise intervention attenuates hyperhomocysteinemia-induced aortic endothelial oxidative injury by regulating SIRT1 through mitigating NADPH oxidase/LOX-1 signaling. Redox Biol2017; 14: 116.
4.
ZhaoQLiDHuangX, et al.Identifying gene–environment interactions on the efficacy of folic acid therapy for hyperhomocysteinemia based on prediction model. Nutr Res2020; 21: 1502–1504.
5.
VezzoliADellanoceCCaimiTM, et al.Influence of dietary supplementation for Hyperhomocysteinemia treatments. Nutrients (2020); 12: 1957.
6.
GlowackiR.Cross-talk between cys34 and lysine residues in human serum albumin revealed by N-homocysteinylation. J Biol Chem2004; 279: 10864–10871.
7.
Perla‐KajanJUtyroORusekM, et al.N-Homocysteinylation impairs collagen cross-linking in cystathionine β-synthase-deficient mice: a novel mechanism of connective tissue abnormalities. FASEB J2016; 20: 1600–1609.
8.
AkchicheNBossenmeyer‐PouriéCKerekR, et al.Homocysteinylation of neuronal proteins contributes to folate deficiency-associated alterations of differentiation, vesicular transport, and plasticity in hippocampal neuronal cells. FASEB J2012; 26: 3980–3982.
9.
YidengJTaoSJiantuanX, et al.Hyperhomocysteinemia-mediated DNA hypomethylation and its potential epigenetic role in Rats. Acta Biochim Biophys Sinica2010; 39: 657–667.
10.
Chuong NguyenMVLardyBPacletMH, et al.Les NADPH oxydases, nox : unenouvelle famille d'isoenzymes. Médecine/ences2015; 31: 43–52.
11.
Cifuentes-PaganoECsanyiGPaganoPJ. NADPH oxidase inhibitors: a decade of discovery from Nox2ds to HTS. Cell Mol Life Sci2012; 69: 2315–2325.
12.
BedardKKrauseKH. The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology. Physiol Rev2007; 87: 245–253.
13.
MasahiroYTakedaK. Role of nuclear IκB proteins in the regulation of host immune responses. J Infect Chemother2008; 14: 265–269.
14.
PolessoFSarkerMAndersonA, et al.Constitutive expression of NF-κB inducing kinase in regulatory T cells impairs suppressive function and promotes instability and pro-inflammatory cytokine production. Scientific Rep2017; 7: 14779.
15.
ProtoJDTangYLuA, et al.NF-κB inhibition reveals a novel role for HGF during skeletal muscle repair. Cell Death Dis2015; 6: e1730.
16.
YanHZQianFHLanHW, et al.High mobility group box 1 protein attenuates myocardial ischemia reperfusion injury via inhibition of the p38 mitogen-activated protein kinase signaling pathway. Exp Ther Med2017; 18: 175–179.
17.
StratowaCAudetteM. Transcriptional regulation of the human intercellular adhesion molecule-1 gene: a short overview. Immunobiology1995; 193: 293–304.
18.
KumasakaTQuinlanWMDoyleNA, et al.Role of the intercellular adhesion molecule-1(ICAM-1) in endotoxin-induced pneumonia evaluated using ICAM-1 antisense oligonucleotides, anti-ICAM-1 monoclonal antibodies, and ICAM-1 mutant mice. J Clin Invest1996; 10: 1001–1002.
MutavdzinSGopcevicKStankovicS, et al. (eds). The effect of folic acid administration on cardiac tissue matrix metalloproteinase activity and hepatorenal biomarkers in diabetic rats 1. In: 5th European Section Meeting of the International Academy of Cardiovascular Sciences, Bratislava, Slovakia, 23–26 May 2018.
21.
LuFZhaoL-YZhangZ-X, et al.The intervention of enalapril maleate and folic acid tablet on the expressions of the GRP78 and CHOP and vascular remodeling in the vascular smooth muscle cells of H-hypertensive rats with homocysteine. Eur Rev Med Pharmacol Sci2018; 25: 527–531.
22.
GilesWHKittnerSJAndaRF, et al.Serum folate and risk for Ischemic Stroke[J]. stroke; a journal of cerebral circulation serum folate and risk for Ischemic Stroke. A J Cereb Circ1995; 26(7): 1166–1171.
23.
MorrisonH. Serum folate and risk of fatal coronary heart disease. J Am Med Assoc1996; 275: 1893–1896.
24.
RimmEBWillettWCHuFB, et al.Folate and vitamin B 6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA1998; 279: 359–364.
25.
WangWWWangX-SZhangZR, et al.A meta-analysis of folic acid in combination with anti-hypertension drugs in patients with hypertension and hyperhomocysteinemia. Front Pharmacol2017; 8: 585–589.
26.
NtaiosGSavopoulosCKaramitsosD, et al.The effect of folic acid supplementation on carotid intima-media thickness in patients with cardiovascular risk: A randomized, placebo-controlled trial. Int J Cardiol2010; 143: 16–19.
27.
TillURhlPJentschA, et al.Decrease of carotid intima-media thickness in patients at risk to cerebral ischemia after supplementation with folic acid, Vitamins B6 and B12. Atherosclerosis2005; 181: 131–135.
28.
AustenSKFassettRGGeraghtyDP, et al.Folate supplementation fails to affect vascular function and carotid artery intima media thickness in cyclosporin A-treated renal transplant recipients. Clin Nephrol2006; 66: 373–379.
29.
TungkasereerakPOng-AjyoothLChaiyasootW, et al.Effect of short-term folate and vitamin B supplementation on blood homocysteine level and carotid artery wall thickness in chronic hemodialysis patients. J Med Assoc Thailand = Chotmaihet Thangphaet2006; 89: 1187–1193.
30.
VielECLemariéCABenkiraneK, et al.Immune regulation and vascular inflammation in genetic hypertension. Am J Physiol2010; 298: 938–944.
31.
DengJJiangCXuQ, et al.Homocysteine Activates B Cells via Regulating PKM2-Dependent Metabolic Reprogramming. J Immunol Official J Am Assoc Immunologists2017; 16: 613–615.
32.
PuFDaqingZZhongjianC, et al.Hyperhomocysteinemia potentiates hyperglycemia-induced inflammatory monocyte differentiation and atherosclerosis. Diabetes2014; 63: 4275–4290.
33.
FamiltsevaAChaturvediPKalaniA, et al.Toll-like Receptor 4 Mutation Suppresses Hyperhomocysteinemia- Induced Hypertension. Am J Physiol Cell Physiol2016; 311: 596–606.
34.
JingLYanZZhangY, et al.GSNOR modulates hyperhomocysteinemia-induced T cell activation and atherosclerosis by switching Akt S-nitrosylation to phosphorylation. Redox Biol2018; 17: 21–28.
35.
XiaomingPJuntianLJingjingZ, et al.Homocysteine induces the expression of C-reactive protein via NMDAr-ROS-MAPK-NF-κB signal pathway in rat vascular smooth muscle cells. Atherosclerosis2014; 236: 73–81.
36.
MakinoEFTWatanabeY. Subacute oral administration of folic acid elicits anti-inflammatory response in a mouse model of allergic dermatitis. J Nutr Biochem2019; 26: 81–89.
37.
RominaLGracielaSDGAlejandraLB, et al.Folate- producing lactic acid bacteria reduce inflammation in mice with induced intestinal mucositis. J Appl Microbiol2018; 16: 91–99.
38.
Van-Der-HeijdenJOerlemansRDijkmansBAC, et al.Folate receptor β as a potential delivery route for novel folate antagonists to macrophages in the synovial tissue of rheumatoid arthritis patients. Arthritis Rheum2010; 60: 12–21.
39.
PaulosCMJo TurkMBreurGJ, et al.Folate receptor-mediated targeting of therapeutic and imaging agents to activated macrophages in rheumatoid arthritis. Adv Drug Deliv Rev2004; 8: 1205–1217.
40.
MaruottiNCantatoreFPCrivellatoE, et al.Macrophages in rheumatoid arthritis. Histol Histopathol2007; 22: 581–586.
41.
KmiećZ. Cooperation of Liver Cells in Health and Disease. Adv Anat Embryol Cell Biol2001; 161: 133–141.
42.
MichaelMZheng-gangL. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res2011; 36: 299–306.
43.
GuestJBilginAHokinB, et al.Novel relationships between B12, folate and markers of inflammation, oxidative stress and NAD(H) levels in the CNS and plasma of a healthy human cohort. Nutr Neuroence2015; 18: 355–364.
44.
VerhaarMCWeverRMFKasteleinJJP, et al.5-Methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation1998; 97: 237–241.
45.
FujikiTAndoFMurakamiK, et al.Tolvaptan activates the Nrf2/HO-1 antioxidant pathway through PERK phosphorylation. Scientific Rep2019; 9: 511–513.
