Hyperhomocysteinemia
(HHcy) is a well-known risk factor for stroke; however, its underlying
molecular mechanism remains unclear. Using both mouse and cell culture
models, we have provided evidence that impairment of autophagy has a
central role in HHcy-induced cellular injury in the mouse brain. We
observed accumulation of LC3B-II and p62 that was associated with
increased MTOR signaling in human and mouse primary astrocyte cell
cultures as well as a diet-induced mouse model of HHcy, HHcy decreased
lysosomal membrane protein LAMP2, vacuolar ATPase (ATP6V0A2), and
protease cathepsin D, suggesting that lysosomal dysfunction also
contributed to the autophagic defect.
Moreover, HHcy increased unfolded protein response (UPR).
Interestingly, Vitamin B supplementation restored autophagic flux, alleviated ER stress, and reversed lysosomal dysfunction due to HHCy.
Furthermore, the autophagy inducer, rapamycin was able to relieve ER stress and reverse lysosomal dysfunction caused by HHcy in vitro.
Inhibition of autophagy by HHcy exacerbated cellular injury during oxygen and glucose deprivation and reperfusion (OGD/R), and oxidative stress. These effects were prevented by Vitamin B co-treatment, suggesting that it may be helpful in relieving detrimental effects of HHcy in ischemia/reperfusion or oxidative stress. Collectively, these findings show that Vitamin B therapy can reverse defects in cellular autophagy and ER stress due to HHcy; and thus may be a potential treatment to reduce ischemic damage caused by stroke in patients with HHcy.
Moreover, HHcy increased unfolded protein response (UPR).
Interestingly, Vitamin B supplementation restored autophagic flux, alleviated ER stress, and reversed lysosomal dysfunction due to HHCy.
Furthermore, the autophagy inducer, rapamycin was able to relieve ER stress and reverse lysosomal dysfunction caused by HHcy in vitro.
Inhibition of autophagy by HHcy exacerbated cellular injury during oxygen and glucose deprivation and reperfusion (OGD/R), and oxidative stress. These effects were prevented by Vitamin B co-treatment, suggesting that it may be helpful in relieving detrimental effects of HHcy in ischemia/reperfusion or oxidative stress. Collectively, these findings show that Vitamin B therapy can reverse defects in cellular autophagy and ER stress due to HHcy; and thus may be a potential treatment to reduce ischemic damage caused by stroke in patients with HHcy.
- PMID:
- 27929536
- PMCID:
- PMC5260994
- DOI:
- 10.1038/cddis.2016.374
- [Indexed for MEDLINE]
Hyperhomocysteinemia (HHcy) is a clinical condition characterized by
increased levels of total plasma homocysteine (Hcy) and carries an
increased risk for stroke.1
Hcy is a methionine precursor and a sulphur amino acid intermediate in
the (re)methylation and trans-sulfuration pathways.
There are three major
dietary cofactors in Hcy metabolism: Vitamin B6, B12,
and folate. Deficiencies in these vitamins were more prevalent in the
developing countries and may account for the increased incidence of HHcy
and stroke found in those countries.2
Additionally, decreased folate, Vitamin B6, and Vitamin B12 plasma levels were associated with HHcy;3
HHcy is frequently categorized into three categories:
moderate (plasma Hcy concentrations of 15–30 μmol/l),
intermediate (plasma Hcy concentrations of 31–100 μmol/l),
and severe (plasma Hcy concentrations 100 μmol/l).6
