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PU.1 inhibition does not attenuate cardiac function deterioration or fibrosis in a murine model of myocardial infarction

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Abstract

Activated cardiac fibroblasts are involved in both reparative wound healing and maladaptive cardiac fibrosis after myocardial infarction (MI). Recent evidence suggests that PU.1 inhibition can enable reprogramming of profibrotic fibroblasts to quiescent fibroblasts, leading to attenuation of pathologic fibrosis in several fibrosis models. The role of PU.1 in acute MI has not been tested. We designed a randomized, blinded study to evaluate whether DB1976, a PU.1 inhibitor, attenuates cardiac function deterioration and fibrosis in a murine model of MI. A total of 44 Ai9 periostin-Cre transgenic mice were subjected to 60 min of coronary occlusion followed by reperfusion. At 7 days after MI, 37 mice were randomly assigned to control (vehicle) or DB1976 treatment and followed for 2 weeks. Left ventricular ejection fraction (EF), assessed by echocardiography, did not differ between the two groups before or after treatment (final EF, 33.3 ± 1.0% in control group and 31.2 ± 1.3% in DB1976 group). Subgroup analysis of female and male mice showed the same results. There were no differences in cardiac scar (trichrome stain) and fibrosis (interstitial/perivascular collagen; picrosirius stain) between groups. Results from the per-protocol dataset (including mice with pre-treatment EF < 35% only) were consistent with the full dataset. In conclusion, this randomized, blinded study demonstrates that DB1976, a PU.1 inhibitor, does not attenuate cardiac functional deterioration or cardiac fibrosis in a mouse model of MI caused by coronary occlusion/reperfusion.

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Data availability

All data and material are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Abbreviations

ECG:

Electrocardiography

EDV:

End-diastolic volume

EF:

Ejection fraction

ESV:

End-systolic volume

I/R:

Ischemia/reperfusion

LV:

Left ventricle

MI:

Myocardial infarction

SV:

Stroke volume

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Acknowledgements

This work was supported in part by National Institutes of Health Grants P01 HL078825 (RB).We thank Dr. Tamer Mohamed for providing animals and materials and input into protocol design.

Funding

This work was supported in part by National Institutes of Health grants P01 HL078825 (RB).

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  1. Yibing Nong and Yiru Guo have contributed equally to the work.

Authors and Affiliations

  1. Institute of Molecular Cardiology, University of Louisville, Louisville, KY, USA

    Yibing Nong, Yiru Guo, Qinghui Ou, Anna Gumpert, Alex Tomlin, Xiaoping Zhu & Roberto Bolli

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  1. Yibing Nong
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  2. Yiru Guo
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  7. Roberto Bolli
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Contributions

RB: designed the experiments, supervised the study, and revised the manuscript. YN: performed the experiments, analyzed data, and wrote the manuscript. YG: performed the experiments, analyzed the data, and supervised data analysis. QO, AG, AT, and XZ: performed experiments and analyzed data.

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Correspondence to Roberto Bolli.

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All animal procedures were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the University of Louisville Institutional Animal Care and Use Committee (protocol number: 14034).

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Nong, Y., Guo, Y., Ou, Q. et al. PU.1 inhibition does not attenuate cardiac function deterioration or fibrosis in a murine model of myocardial infarction. Mol Cell Biochem 478, 927–937 (2023). https://doi.org/10.1007/s11010-022-04561-7

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