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Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk
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Targeting transcription in heart failure via CDK7/12/13 inhibition

Austin Hsu1,2, Qiming Duan1, Daniel S Day3

  • 1Gladstone Institutes, San Francisco, CA, USA.

Nature Communications
|July 27, 2022
PubMed

Insights

New research identifies CDK7/12/13 as key targets for treating heart failure with reduced ejection fraction (HFrEF). Inhibiting these transcription regulators with THZ1 shows promise in preclinical models for improving cardiac function.

Area of Science:

  • Cardiovascular Biology
  • Molecular Biology
  • Pharmacology

Background:

  • Heart failure with reduced ejection fraction (HFrEF) presents a significant mortality challenge, necessitating novel therapeutic interventions.
  • Stress-induced signaling pathways in the heart converge on nuclear transcription, driving detrimental gene expression patterns.
  • Targeting pathological transcription offers a promising therapeutic strategy for HFrEF.

Purpose of the Study:

  • To investigate the role of CDK7/12/13 in cardiac transcription during HFrEF.
  • To evaluate the therapeutic potential of inhibiting CDK7/12/13 for HFrEF treatment.

Main Methods:

  • Utilized RNA interference (RNAi) and the small molecule inhibitor THZ1 to target CDK7/12/13.
  • Assessed effects in cultured rodent cardiomyocytes and in vivo mouse models of HFrEF.
  • Examined human induced pluripotent stem cell (iPSC)-derived cardiomyocytes.

Main Results:

  • CDK7/12/13 inhibition blocked stress-induced transcription and pathological hypertrophy in cardiomyocytes.
  • THZ1 treatment attenuated adverse cardiac remodeling and HFrEF progression in mice.
  • THZ1 suppressed RNA Polymerase II enrichment at stress-activated cardiac genes and a specific pathological gene program in failing hearts.
  • THZ1 demonstrated efficacy in human iPSC-derived cardiomyocytes.

Conclusions:

  • CDK7/12/13 are critical regulators of cardiac gene transactivation under stress.
  • Pharmacological inhibition of CDK7/12/13 represents a druggable target for HFrEF.
  • HFrEF exhibits a dependency on transcription that can be therapeutically exploited via CDK7/12/13 inhibition.

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