What is the clinical evidence from this study?

Study design: Other. Population: Hypertensive heart failure and cardiac remodeling. Intervention: CDK9 inhibitor NVP2 vs. Vehicle. Primary outcome: Cardiac hypertrophy, fibrosis, and dysfunction.

What question did this study set out to answer?

This research aims to investigate the role of CDK9 in cardiac inflammation and remodeling mechanisms in hypertrophic cardiomyocytes.

March 26, 2026Nature Communications1 citationsOpen Access

Cardiomyocyte Cyclin-dependent kinase 9 directly binds to and phosphorylates NF-κB p65 subunit to drive cardiac inflammation and remodeling

Q: What does this research mean for the field?

Pharmacological inhibition or genetic inactivation of CDK9 at Thr-186 significantly attenuates Ang II-induced cardiac inflammation, remodeling, and dysfunction in mice. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

SYS. Ye YZYi Zhao HTHanxiao Tu

Key Result

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.

Key Points

This research aims to investigate the role of CDK9 in cardiac inflammation and remodeling mechanisms in hypertrophic cardiomyocytes.
Identified the phosphorylation state of CDK9 at Thr-186 in human and mouse hypertrophic heart tissues.
Utilized T186A and T186E mutations to assess the functional role of CDK9 in cardiomyocytes under Ang II stimulation.
Conducted pharmacological inhibition of CDK9 to observe effects on cardiac inflammation and remodeling.
CDK9 phosphorylates NF-κB p65 at Thr-186, promoting cardiac inflammation and remodeling.
Loss of CDK9 function attenuates Ang II-induced inflammatory responses in cardiomyocytes.
Pharmacological inhibition of CDK9 significantly reduces cardiac dysfunction in mice exposed to Ang II.

Structured PICO

Does pharmacological inhibition or genetic inactivation of CDK9 reduce Ang II-induced cardiac inflammation and remodeling in preclinical models?

Population

Preclinical models including human hypertrophic heart tissues, mouse models of Ang II-induced cardiac remodeling (Ang II infusion for 4 weeks), neonatal rat ventricular myocytes (NRVMs), and 293T cells.

Intervention

CDK9 loss of function (T186A mutation, siCDK9), CDK9 overactivation (T186E mutation), and pharmacological inhibition of CDK9 using NVP2 (5 mg/kg/day, intraperitoneally for the final 2 weeks of a 4-week Ang II challenge).

Comparator

Vehicle, wild-type CDK9 (CDK9WT), or negative control siRNA.

Outcome

Cardiac inflammation, remodeling, and dysfunction (assessed via echocardiography, histology for hypertrophy and fibrosis, and molecular markers of NF-κB P65 pathway activation).surrogate

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.

Limitations

The mechanism by which the Ang II-AT1R axis mediates CDK9 phosphorylation deserves further investigation.

Abstract

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.

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