15 February 2020 by Guanming Qi

Myeloid mineralocorticoid receptor contributes to lung inflammation and vascular remodelling in experimental pulmonary hypertension

Objective: Previous studies have indicated that mineralocorticoid receptor (MR) regulates systemic vascular function and contributes to cardiovascular disease by promoting cell proliferation and fibrosis, but the underlying mechanism remains unclear. We hypothesize that myeloid-MR plays a pivotal role in the cross-talk between macrophages (MØs) and pulmonary fibroblasts, promoting pulmonary inflammation-mediated vascular remodeling of pulmonary hypertension (PH).

Methods: Male myeloid-specific MR knockout (MyMR-KO) mice and their littermate controls (MyMR-intact) were exposed to Sugen5416(Su)/hypoxia to induce PH or normoxia for 4 weeks. We measured right ventricular (RV) hemodynamics, cardiomyocyte size, pulmonary vascular muscularization and collagen deposition, and perivascular lung inflammation. In vitro, human pulmonary adventitial fibroblasts (hFibs) were treated with conditioned medium from MyMR-KO MØs (vs. MyMR-intact) and expression of profibrotic genes was measured.

Results: SU/hypoxia produced similar increases in RV systolic pressure and RV mass in both MyMR-KO and MyMR-intact mice. However, MyMR-KOs showed attenuated pulmonary vascular remodeling compared with MyMR-intact mice with decreased muscularization and arterial wall collagen deposition. RV cardiomyocyte area was also reduced in MyMR-KO mice. Moreover, lung inflammation was attenuated in MyMR-KO mice with down-regulation of TNFα expression and reduced infiltration of Galectin-3 (Gal-3) positive cells in the lungs compared to MyMR-intact mice. When exposed to conditioned medium from MyMR-KO MØs, cultured hFibs significantly decreased mRNA expression of profibrotic genes: collagen Iα1 (Col IA1), transglutaminase 2 (TG2) and α-smooth muscle actin (α-SMA), but not Ki67, a proliferative gene.

Conclusions: Our results suggest that MR in MØs contributes to experimental PH via increased accumulation of Gal-3 positive inflammatory cells in the perivascular area, followed by production of paracrine factors that activate adventitial fibroblasts towards a profibrotic phenotype

 

About the author


profile picture of Guanming Qi

Guanming Qi

Research fellow

Tufts Medical Center

United States

Key Contributors

Guanming Qi, Rod R. Warburton, Krishna C. Penumatsa, Mary E. Moss, Joshua Man, Qing Lu, Seung Kyum Kim, Nicholas S. Hill1, Iris Z. Jaffe, Ioana R. Preston Pulmonary, Critical Care and Sleep Division, Tufts Medical Center, Boston, MA; Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA


Comments (0)

Our research platform is the world.

Through worldwide collaboration, we can begin to answer the question of a global disease.

Join the PVRI
standard-example-image.jpg