α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension

Alexander Vang, Denielli da Silva Gonçalves Bos, Ana Fernandez-Nicolas, Peng Zhang, Alan R. Morrison, Thomas J. Mancini, Richard T. Clements, Iuliia Polina, Michael W. Cypress, Bong Sook Jhun, Edward Hawrot, Ulrike Mende, Jin O-Uchi, Gaurav Choudhary

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Right ventricular (RV) fibrosis is a key feature of maladaptive RV hypertrophy and dysfunction and is associated with poor outcomes in pulmonary hypertension (PH). However, mechanisms and therapeutic strategies to mitigate RV fibrosis remain unrealized. Previously, we identified that cardiac fibroblast α7 nicotinic acetylcholine receptor (α7 nAChR) drives smoking-induced RV fibrosis. Here, we sought to define the role of α7 nAChR in RV dysfunction and fibrosis in the settings of RV pressure overload as seen in PH. We show that RV tissue from PH patients has increased collagen content and ACh expression. Using an experimental rat model of PH, we demonstrate that RV fibrosis and dysfunction are associated with increases in ACh and α7 nAChR expression in the RV but not in the left ventricle (LV). In vitro studies show that α7 nAChR activation leads to an increase in adult ventricular fibroblast proliferation and collagen content mediated by a Ca2+/epidermal growth factor receptor (EGFR) signaling mechanism. Pharmacological antagonism of nAChR decreases RV collagen content and improves RV function in the PH model. Furthermore, mice lacking α7 nAChR exhibit improved RV diastolic function and have lower RV collagen content in response to persistently increased RV afterload, compared with WT controls. These finding indicate that enhanced α7 nAChR signaling is an important mechanism underlying RV fibrosis and dysfunction, and targeted inhibition of α7 nAChR is a potentially novel therapeutic strategy in the setting of increased RV afterload.

Original languageEnglish (US)
Article numbere142945
JournalJCI Insight
Volume6
Issue number12
DOIs
StatePublished - Jun 22 2021

Bibliographical note

Funding Information:
The authors would like to thank Serpil Erzurum, Learner Institute of Cleveland Clinic, for providing specimens of human hearts; Amanda Costa Sousa for her assistance with echocardiography data acquisition; Nouaying R. Kue, Alexander Park, and Julia Feord for technical support; and Phu Tran at University of Minnesota for TMEM35/NACHO plasmid. This material was the result of work supported with resources and the use of facilities at the Providence VA Medical Center and the CPVB (under grant P20GM103652). GC was supported by NHLBI R01HL128661, VA BLSR&D grant I01CX001892, and NHLBI R01HL148727. ARM was supported by NHLBI R01HL139795 and NIGMS P20GM103652. JO is supported by NIH R01HL136757 and P30GM1114750. UM was supported by NHLBI R01HL114784. BSJ was supported by AHA 18CDA34110091. RTC was supported by NHLBI R01HL135236. The views expressed in this article are those of the authors and do not reflect the position nor policy of the Department of Veterans Affairs and the NIH.

Publisher Copyright:
© 2021, Vang et al.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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