Mechanism by Which Inflammation and Oxidative Stress Induce Mineralocorticoid Receptor Gene Expression in Aging...

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Aging Research

Background:

• Vascular mineralocorticoid receptor (MR) expression escalates with age, contributing to vascular stiffness and hypertension.
• The gene regulatory mechanisms governing MR expression, particularly its isoforms (1α and 1β), remain largely unelucidated in aging vascular cells.

Purpose of the Study:

• To investigate the transcriptional regulation mechanisms of the MR gene in aging human smooth muscle cells (SMCs).
• To identify key transcription factors involved in MR gene regulation during cellular aging.

Main Methods:

• Quantified MR expression in aged human aortic tissues and primary human aortic SMCs (HASMCs).
• Utilized H₂O₂ treatment to induce aging in HASMCs.
• Validated predicted transcription factor (TF) binding sites using chromatin immunoprecipitation and reporter assays.
• Examined the effects of TF inhibitors on MR isoforms and fibrosis-related gene expression.

Main Results:

• MR mRNA isoforms (1α and 1β) increased with donor age and H₂O₂-induced aging in HASMCs.
• Hypoxia-inducible factor 1-alpha (HIF1α) and nuclear factor kappa B (NFκB) expression and DNA binding increased with age and H₂O₂ treatment.
• HIF1α inhibition reduced MR-1α, while NFκB inhibition reduced both MR isoforms.
• Inhibition of HIF1α, NFκB, and MR decreased expression of a vascular fibrosis-associated gene.
• HIF1α and NFκB expression positively correlated with age and MR expression in human aortic tissues.

Conclusions:

• The inflammatory TF NFκB and oxidative stress-induced TF HIF1α are implicated in regulating SMC MR transcription during aging.
• This regulatory pathway contributes to aging-related vascular stiffness and cardiovascular disease.
• Targeting NFκB and HIF1α may offer therapeutic strategies for age-related vascular dysfunction.