학술논문
NFATc3 regulation of collagen V expression contributes to cellular immunity to collagen type V and hypoxic pulmonary hypertension.
Document Type
Academic Journal
Author
Sheak JR; Department of Cell Biology and Physiology, Vascular Physiology Group, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.; Jones DT; Department of Cell Biology and Physiology, Vascular Physiology Group, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.; Lantz BJ; Department of Cell Biology and Physiology, Vascular Physiology Group, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.; Maston LD; Department of Cell Biology and Physiology, Vascular Physiology Group, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.; Vigil D; Department of Cell Biology and Physiology, Vascular Physiology Group, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.; Resta TC; Department of Cell Biology and Physiology, Vascular Physiology Group, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.; Resta MM; Department of Cell Biology and Physiology, Vascular Physiology Group, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.; Howard TA; Department of Cell Biology and Physiology, Vascular Physiology Group, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.; Kanagy NL; Department of Cell Biology and Physiology, Vascular Physiology Group, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.; Guo Y; Department of Internal Medicine, Bioinformatics Shared Resource Center, Division of Molecular Medicine, University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.; Jankowska-Gan E; Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.; Sullivan JA; Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.; Braun RK; Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.; Burlingham WJ; Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.; Gonzalez Bosc LV; Department of Cell Biology and Physiology, Vascular Physiology Group, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
Source
Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901229 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1504 (Electronic) Linking ISSN: 10400605 NLM ISO Abbreviation: Am J Physiol Lung Cell Mol Physiol Subsets: MEDLINE
Subject
Language
English
Abstract
Chronic hypoxia (CH)-induced pulmonary hypertension (PH) results, in part, from T helper-17 (T H 17) cell-mediated perivascular inflammation. However, the antigen(s) involved is unknown. Cellular immunity to collagen type V (col V) develops after ischemia-reperfusion injury during lung transplant and is mediated by naturally occurring (n)T H 17 cells. Col5a1 gene codifies for the α1-helix of col V, which is normally hidden from the immune system within type I collagen in the extracellular matrix. COL5A1 promoter analysis revealed nuclear factor of activated T cells, cytoplasmic 3 (NFATc3) binding sites. Therefore, we hypothesized that smooth muscle NFATc3 upregulates col V expression, leading to nT H 17 cell-mediated autoimmunity to col V in response to CH, representing an upstream mechanism in PH development. To test our hypothesis, we measured indexes of PH in inducible smooth muscle cell (SMC)-specific NFATc3 knockout (KO) mice exposed to either CH (380 mmHg) or normoxia and compared them with wild-type (WT) mice. KO mice did not develop PH. In addition, COL5A1 was one of the 1,792 genes differentially affected by both CH and SMC NFATc3 in isolated intrapulmonary arteries, which was confirmed by RT-PCR and immunostaining. Cellular immunity to col V was determined using a trans vivo delayed-type hypersensitivity assay (Tv-DTH). Tv-DTH response was evident only when splenocytes were used from control mice exposed to CH but not from KO mice, and mediated by nT H 17 cells. Our results suggest that SMC NFATc3 is important for CH-induced PH in adult mice, in part, by regulating the expression of the lung self-antigen COL5A1 protein contributing to col V-reactive nT H 17-mediated inflammation and hypertension.