Rapid onset fibrotic remodeling and ventricular dysfunction induced by phenylephrine involve targeted reprogramming of myocyte and fibroblast transcriptomes.

Autor:	Kimball TH; Departments of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine., Gromova T; Departments of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine., Gehred ND; Departments of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine., Chapski DJ; Departments of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine., Wang K; Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles., Vaseghi M; Cardiac Arrhythmia Center, Division of Cardiology, Department of Medicine, University of California, Los Angeles., Fischer MA; Departments of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine., Lefer DJ; Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles., Vondriska TM; Departments of Anesthesiology & Perioperative Medicine, David Geffen School of Medicine.; Physiology, David Geffen School of Medicine.; Medicine, David Geffen School of Medicine.; Molecular Biology Institute, University of California, Los Angeles.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Oct 15. Date of Electronic Publication: 2024 Oct 15.
DOI:	10.1101/2024.10.11.617933
Abstrakt:	Catecholamine dysregulation is a common feature of multiple acute and chronic cardiac conditions, including heart failure. To investigate the role of altered α-adrenergic stimulation on cardiac function, we developed a short-term exposure model, administering phenylephrine subcutaneously to mice for one week. Compared to vehicle-injected controls, phenylephrine-treated animals exhibited increased ejection fraction, decreased chamber size, diastolic dysfunction and ventricular hypertrophy in the absence of hypertension. Remarkably, these animals developed extensive fibrotic remodeling of the tissue that plateaued at 24 hours and myocyte hypertrophy localized to regions of fibrotic deposition after 3 days of treatment. Transcriptome analyses of purified myocyte and fibroblast populations from these hearts revealed an unexpected role for myocytes in the production of extracellular matrix. Comparison with other models of cardiac stress, including pressure overload hypertrophy and cytokine activation of fibroblasts, identified stimulus-specific transcriptional circuits associated with cardiac pathology. Given the rapid, robust fibrotic response that preceded myocyte hypertrophy, intercellular communication analyses were conducted to investigate fibroblast to myocyte signaling, identifying potential crosstalk between these cells. These studies thoroughly describe and phenotypically characterize a new model of short-term catecholamine stress and provide an atlas of transcriptional remodeling in myocytes and fibroblasts. Competing Interests: Competing Interest The authors declare no competing interests.
Databáze:	MEDLINE
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