Investigating novel mechanisms of PKGI activation and their impact on the cardiovascular system

Abstract

The major cytosolic DNA sensor GMP-AMP synthase (cGAS) has emerged as a key mediator of inflammation that underlies cardiovascular disease. Upon interaction with double stranded DNA, cGAS generates the second messenger 2’3’cyclic GMP-AMP (cGAMP) that directly binds to and activates stimulator of interferon genes (STING), which in turn leads to enhanced expression of genes encoding interferons and proinflammatory cytokines. This study led to the discovery that cGAMP directly activates PKGI, establishing a crosstalk between inflammation and blood pressure regulation. Methods, including molecular, cellular, and biochemical analyses, were used to assess how cGAS and cGAMP activate PKGI. Results show that cGAMP is released from the endothelium and imported into vascular smooth muscle cells, leading to PKGI activation and vasorelaxation. This mechanism enables the coupling of blood pressure to cytosolic DNA sensing by cGAS, which plays a key role during sepsis by mediating hypotension and tissue hypoperfusion.

In a further study, the redox-dependent activation of PKGIα was targeted as a potential therapy for treating heart failure with preserved ejection fraction (HFpEF). PKGIα is a redox-sensitive kinase that can be activated by oxidation through the formation of an intermolecular disulfide between two monomers. Through various methods, including molecular, cellular, and in vivo analyses, the ability of urolithin A to induce PKGIα oxidative activation was assessed, as well as the importance of this process in limiting HFpEF. Our results reveal that urolithin A alleviates cardiovascular dysfunction in a model of HFpEF, thus providing a promising new strategy for therapy.

In summary, our work provides insight into novel mechanisms of PKGI activation that regulate blood pressure and cardiac function, which can be targeted for therapy, thus addressing crucial aspects of cardiovascular health and disease management.

Date of Award	1 Jul 2024
Original language	English
Awarding Institution	King's College London
Supervisor	Joe Burgoyne (Supervisor)