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.

Folate Reverses NF-κB p65/Rela/IL-6 Level Induced by Hyperhomocysteinemia in Spontaneously Hypertensive Rats.

Hyperhomocysteinemia (HHcy) is derived from the abnormal metabolism of homocysteine (Hcy) and is related to metabolic-related diseases. In addition, HHcy combined with hypertension increases the risk of cardiovascular diseases (CVD). However, the mechanism of HHcy aggravating hypertensive arterial damage and the efficacy of folate (FA) as a beneficial supplement have not been fully elucidated. In this study, we established a rat HHcy model and a hypertension combined with HHcy model. Rat tail artery blood pressure (BP), plasma Hcy, serum superoxide dismutase (SOD), and malondialdehyde (MDA) were measured. Rat thoracic aorta was for pathological analysis after 12 weeks of the experiment. The relative expression levels of oxidative stress and immune/inflammation in rat arterial tissues were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. The results demonstrated that the relative expression levels of oxidative stress and immune/inflammation were the highest in the hypertension combined with HHcy group, followed by the hypertension group. Compared with the hypertension group, the hypertension combined with HHcy group up-regulated the expression levels of interleukin-6 (IL-6) and nuclear factor-κ-gene binding (NF-κB) p65/Rela, but not NADPH oxidase (Nox). Furthermore, folate inhibited the expression of IL-6 and NF-κB p65/Rela, reduced the levels of MDA and HHcy, but significantly increased the SOD level. In conclusion, HHcy synergistically aggravated the arterial damage factor of hypertension through immune/inflammatory response. However, folate demonstrated anti-inflammatory properties and reversed the NF-κB p65/Rela/IL-6 level induced by HHcy in hypertensive rats.