m6A reader YTHDF3 elicits hypertensive effects by degrading XRCC1 mRNA in the rostral ventrolateral medulla

Area of Science:

• Molecular Biology
• Neuroscience
• Cardiovascular Research

Background:

• N6-methyladenosine (m6A) modification is implicated in various diseases.
• The rostral ventrolateral medulla (RVLM) is vital for blood pressure regulation.
• The role of m6A regulators like YTHDF3 in the RVLM and hypertension is unclear.

Purpose of the Study:

• Investigate the role of YTHDF3 in the RVLM of spontaneously hypertensive rats (SHRs).
• Elucidate the mechanism by which YTHDF3 influences hypertension.
• Determine the therapeutic potential of targeting the YTHDF3-XRCC1 pathway.

Main Methods:

• Compared YTHDF3 levels in the RVLM of SHRs and WKY rats.
• Performed YTHDF3 knockdown in the RVLM of SHRs.
• Assessed neuronal excitability, sympathetic tone, and blood pressure.
• Investigated the interaction between YTHDF3, XRCC1 mRNA, and DNA damage repair.
• Utilized in vitro and in vivo models, with and without XRCC1 inhibition.

Main Results:

• YTHDF3 levels were elevated in the RVLM of SHRs.
• YTHDF3 knockdown reduced neuronal excitability, sympathetic tone, and blood pressure.
• YTHDF3 promoted XRCC1 mRNA degradation in an m6A-dependent manner.
• YTHDF3 inhibition enhanced XRCC1 expression, DNA repair, and reduced apoptosis.
• XRCC1 inhibition reversed the antihypertensive effects of YTHDF3 knockdown.

Conclusions:

• YTHDF3 is a key regulator in the neural control of hypertension via the RVLM.
• The YTHDF3-XRCC1 axis influences neuronal function and blood pressure.
• Targeting the YTHDF3-XRCC1 pathway in the RVLM is a potential therapeutic strategy for hypertension.