Pharmacological inhibition of CDK9 with NVP2 or genetic inactivation of its Thr-186 phosphorylation significantly attenuated Ang II-induced cardiac inflammation, remodeling, and dysfunction in mice.
Does pharmacological inhibition or genetic inactivation of CDK9 reduce Ang II-induced cardiac inflammation and remodeling in preclinical models?
CDK9 directly binds to and phosphorylates the NF-κB p65 subunit to drive cardiac inflammation and remodeling, highlighting CDK9 as a potential therapeutic target for hypertensive heart failure.
Hypertensive heart failure highlights an urgent need for effective therapeutic strategies. Protein kinases regulate multiple pathways in cardiac pathophysiology and may provide promising therapeutic targets. Here, we identified a Cyclin-dependent kinase, CDK9, promoting inflammation and cardiac remodeling in terminally differentiated cardiomyocytes. Firstly, kinase enrichment analysis and experimental evidence revealed CDK9 phosphorylation at Thr-186 in both human and mouse hypertrophic heart tissues. CDK9 loss of function via T186A mutation in cardiomyocytes attenuated Ang II-induced heart remodeling and NF-κB-mediated inflammation, whereas CDK9 overactivation by T186E mutation induces. This regulatory function of CDK9 in cardiac remodeling is cell cycle-independent. Further studies demonstrate that the kinase domain of CDK9 directly binds to NF-κB P65 protein, which leads to the CDK9/P65 complex nuclear translocation, P65 phosphorylation, and transcription of inflammatory and hypertrophic genes in cardiomyocytes. This process requires CDK9 Thr-186 phosphorylation and Cyclin T1 presence, but is independent on IKKβ and CDK9-RNAPII pathways. Pharmacological inhibition of CDK9 phosphorylation significantly attenuated Ang II-induced cardiac inflammation, remodeling, and dysfunction in mice. Collectively, Ang II-activated CDK9 directly binds to and phosphorylates P65 to drive cardiac inflammation and remodeling. This study identifies CDK9 as a potential target in heart failure therapeutics. Liang Guang et al revealed that cardiac CDK9 is activated in hypertrophic myocardium and directly binds to NF-κB P65, promoting its phosphorylation to drive inflammation and remodeling. This finding identifies CDK9 as a potential therapeutic target for hypertrophic cardiomyopathy.
Ye et al. (2026) studied Hypertensive heart failure and cardiac remodeling. CDK9 inhibitor NVP2 vs. Vehicle was evaluated on Cardiac hypertrophy, fibrosis, and dysfunction. Pharmacological inhibition of CDK9 with NVP2 or genetic inactivation of its Thr-186 phosphorylation significantly attenuated Ang II-induced cardiac inflammation, remodeling, and dysfunction in mice.