Regulation of DNA damage and transcriptional output in the vasculature through a cytoglobin-HMGB2 axis

Area of Science:

• Vascular Biology
• Molecular Medicine
• Biochemistry

Background:

• Cardiovascular diseases necessitate identifying novel regulators of vascular smooth muscle cell (VSMC) function.
• Cytoglobin (CYGB), a hemoglobin homolog, exhibits myogenic and cytoprotective roles in the vasculature.
• CYGB's precise mechanism of action, distinct from oxygen transport, remains unclear.

Purpose of the Study:

• To elucidate the mechanism of action of cytoglobin in VSMC function.
• To investigate the role of cytoglobin in regulating gene expression and DNA damage in the vasculature.
• To determine the cellular localization and interaction partners of cytoglobin.

Main Methods:

• Transcriptomic profiling of injured carotid arteries in cytoglobin global knockout (KO) mice.
• Analysis of DNA damage markers in VSMCs.
• Cellular fractionation and immunofluorescence to track cytoglobin localization.
• Co-immunoprecipitation assays to identify protein interaction partners.

Main Results:

• Cytoglobin deletion in mice accelerated the loss of contractile genes and increased DNA damage in injured carotid arteries.
• Cytoglobin is actively translocated into the nucleus of VSMCs, driven by a redox signal from NOX4.
• Nuclear cytoglobin heterodimerizes with the chromatin structural protein HMGB2.
• Cytoglobin modulates genome-wide HMGB2 binding, inhibiting DNA damage and regulating gene programs.

Conclusions:

• Cytoglobin functions beyond oxygen transport, acting as a nuclear regulator in VSMCs.
• Cytoglobin plays a critical role in maintaining genomic stability and regulating gene expression in the vasculature.
• This discovery reveals a novel mechanism for non-erythrocytic hemoglobins in cardiovascular health and disease.