Targeting C42 in PKGIα alleviates diastolic dysfunction in HFpEF
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Background
In our exploration of novel therapeutic strategies for treating heart failure with preserved ejection fraction (HFpEF), we focused on cysteine 42 (C42) in cGMP-dependent protein kinase Iα (PKGIα), which plays a crucial role in regulating blood pressure and diastolic relaxation. Our findings demonstrate that targeting C42 on PKGIα with urolithin A effectively limits diastolic dysfunction and cardiac remodeling in a multi-hit mouse model of HFpEF, while also improving the kinetics of relaxation and contraction in human-engineered heart tissue.
Methods
We evaluated various polyphenols, including urolithin A, for their capacity to oxidize and activate PKGIα. This assessment involved recombinant protein, isolated rat aortic smooth muscle cells, and myography experiments using isolated mesenteric vessels. Additionally, we investigated the ability of urolithin A to stimulate PKGIα-dependent phosphorylation of phospholamban (PLN) in neonatal rat ventricular myocytes (NRVMs). A multi-hit mouse model was employed to induce HFpEF in wild-type and C42S PKGIα knock-in (KI) mice. Following this, the mice were given vehicle or urolithin A by gavage, and heart function was evaluated using echocardiography. The relevance to human physiology was assessed using human-engineered heart tissue.
Results
The polyphenols quercetin, fisetin, and urolithin A were shown to induce C42-dependent activation of PKGIα. This mechanism of kinase activation led to vasorelaxation, which was attenuated in mesenteric vessels isolated from KI mice. Additionally, urolithin A treatment promoted PKGI-dependent phosphorylation of phospholamban in isolated cardiomyocytes. In a multi-hit model of HFpEF, urolithin A reversed diastolic dysfunction and cardiac remodeling in wild-type mice, but not in KI mice. These findings were shown to be likely relevant to humans, as urolithin A also enhanced the kinetics of relaxation and contraction in human-engineered heart tissue.
Conclusions
Targeting C42 in PKGIα with urolithin A presents a promising new strategy for the treatment of HFpEF.
