Inhibition of Cyclic GMP-AMP Synthase Ameliorates Cardiac Dysfunction in Rats After Cardiac Arrest
Cardiac dysfunction is a prevalent and serious complication after cardiac arrest (CA), yet limited therapeutic interventions are available. Cyclic GMP-AMP synthase (cGAS), a critical mediator of innate immune responses, has recently been identified as a potential contributor to cardiac dysfunction....
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Compuscript Ltd
2025-04-01
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| Series: | Cardiovascular Innovations and Applications |
| Online Access: | https://www.scienceopen.com/hosted-document?doi=10.15212/CVIA.2025.0010 |
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| Summary: | Cardiac dysfunction is a prevalent and serious complication after cardiac arrest (CA), yet limited therapeutic interventions are available. Cyclic GMP-AMP synthase (cGAS), a critical mediator of innate immune responses, has recently been identified as a potential contributor to cardiac dysfunction. This study was aimed at investigating the role of cGAS in post-CA cardiac dysfunction. In vivo , in rats with ventricular fibrillation (VF)-induced CA, a selective cGAS inhibitor (RU.521) was used to specifically inhibit cGAS activity, thereby blocking its downstream signaling pathway. In vitro , hypoxia and reoxygenation (H/R) were used to stimulate H9C2 cardiomyocytes, and a specific siRNA targeting cGAS was applied to knock down cGAS expression. Our comprehensive analysis revealed significant upregulation of cGAS protein expression and activation of the cGAS-STING pathway in both myocardial tissues of rats that achieved ROSC and H/R-stimulated H9C2 cells. Pharmacological inhibition of cGAS with RU.521 effectively ameliorated cardiac function and maintained hemodynamic stability in ROSC rats. Genetic knockdown of cGAS enhanced the resistance of H9C2 cells to H/R-induced cell injury. Mechanistically, cGAS inhibition effectively attenuated CA-induced mitochondrial injury while concurrently suppressing oxidative stress and apoptosis. These findings highlight a strong association between cGAS upregulation and cardiac dysfunction after CA. Targeting cGAS might provide a promising therapeutic strategy for improving cardiac function in patients with CA. |
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| ISSN: | 2009-8618 2009-8782 |