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Smooth Muscle NFATc3 Contributes to Chronic Hypoxia‐induced Pulmonary Hypertension
Author(s) -
Sheak Joshua R,
Maston Levi D,
Giermakowska Wieslawa,
Jones David T,
Resta Thomas C,
Bosc Laura V Gonzalez
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1073.6
Subject(s) - ventricle , pulmonary hypertension , medicine , right ventricular hypertrophy , endocrinology , muscle hypertrophy , hypoxia (environmental) , ventricular pressure , tamoxifen , chemistry , pulmonary artery , biology , blood pressure , oxygen , organic chemistry , cancer , breast cancer
We have previously demonstrated that global nuclear factor of activated T cells isoform 3 (NFATc3) knockout (KO) mice are protected from chronic hypoxia (CH)‐induced pulmonary hypertension (PH). However, the role of smooth muscle (SM) NFATc3 in this response has not been explored. We hypothesized that inducible‐smooth muscle‐specific NFATc3 KO (SMC‐NFATc3 KO) mice are protected from CH‐induced PH. After 21 days of normoxia (630 mmHg) or CH (380 mmHg) exposure, right ventricular systolic pressure (RVSP) was recorded in isoflurane‐anesthetized wild type (WT) mice, in B6.FVB‐Tg(Myh11‐cre/ERT2)1Soff/J (SMC‐Cre) and SMC‐Cre mice crossed with NFATc3 fl/fl (SMC‐NFATc3 KO) mice fed either a regular diet or a diet containing tamoxifen. Fulton's index (right ventricle/left ventricle plus septum weight) and % pulmonary arterial wall thickness were also determined as indices of right ventricular hypertrophy and pulmonary vascular remodeling, respectively. We observed that CH exposure increased RVSP in WT mice, in SMC‐NFATc3 KO mice on a regular diet, and in SMC‐Cre mice fed either a regular or tamoxifen diet (*p<0.05 vs. respective normoxic control). In contrast, SMC‐NFATc3 KO mice treated with tamoxifen were protected from the development of CH‐induced PH (#p<0.05 vs. all other CH groups). Similar changes were observed for Fulton's index and % pulmonary arterial wall thickness. In conclusion, knocking out NFATc3 in SM in adult mice inhibits the development of PH in response to CH suggesting that NFATc3 regulates the expression of genes that contribute to the pathogenesis of PH. Support or Funding Information NIH F31 HL131334 for JRS. NIH F30 HL123109 for LDM. NIH R01 HL132883 and AHA 16GRNT27700010 for TCR. AHA 15GRNT25090039 for LVGB.*p<0.05 vs. normoxia, #p<0.05 vs. all CH groups, n=5–6