Sensing Cytosolic DNA Lowers Blood Pressure by Direct cGAMP-Dependent PKGI Activation

Area of Science:

• Cardiovascular Biology
• Immunology
• Molecular Medicine

Background:

• Cyclic GMP-AMP synthase (cGAS) is a key cytosolic DNA sensor involved in inflammation.
• cGAS activation by DNA generates 2',3'-cyclic GMP-AMP (cGAMP), which stimulates interferon production and inflammatory cytokines.
• This study investigates a novel role for cGAMP in cardiovascular regulation.

Purpose of the Study:

• To elucidate the mechanism by which cGAMP influences blood pressure regulation.
• To determine the role of cGAMP in crosstalk between inflammation and cardiovascular function.
• To investigate the direct activation of PKGI by cGAMP.

Main Methods:

• Utilized molecular, cellular, and biochemical analyses to assess cGAS and cGAMP activity.
• Employed myography experiments to evaluate vascular responses.
• Measured cGAMP release and uptake using ELISA and transporter identification.
• Assessed blood pressure in wild-type and cGAS knockout mice using telemetry.

Main Results:

• cGAMP generated by cGAS in vascular endothelium is extruded by MRP1 and imported into vascular smooth muscle cells via the volume-regulated anion channel.
• cGAMP directly activates PKGI, mediating vasorelaxation independently of the nitric oxide pathway.
• This PKGI activation lowers blood pressure, contributing to hypotension during sepsis.

Conclusions:

• cGAMP-PKGI activation couples cytosolic DNA sensing by cGAS to blood pressure regulation.
• This pathway is crucial in sepsis, mediating hypotension and tissue hypoperfusion.
• Identified a novel signaling axis linking innate immunity and cardiovascular homeostasis.