TY - JOUR
T1 - Hyperoxia and transforming growth factor β1 signaling in the post-ischemic mouse heart
AU - Li, Yuanjing
AU - Cai, Ming
AU - Sun, Qinghua
AU - Liu, Zhenguo
AU - Cardounel, Arturo J.
AU - Swartz, Harold M.
AU - He, Guanglong
N1 - Funding Information:
This work was supported by the National Institutes of Health [Grant HL081630 to G.H., ES016588 and ES018900 to Q.S., HL094650 to Z.L., and HL081734 to A.J.C.]; Diabetic Action Research and Education Foundation Grant to G.H.; and the University of Texas at Austin [ UTA11-000297 to A.J.C.]. The LiPc was made with the support of PO1 EB2180 (H.M.S).
PY - 2013
Y1 - 2013
N2 - Aims Following ischemic injury, myocardial healing and remodeling occur with characteristic myofibroblast trans-differentiation and scar formation. The current study tests the hypothesis that hyperoxia and nitric oxide (NO) regulate TGF-β1 signaling in the post-ischemic myocardium. Main methods C57BL/6 wild-type (WT), endothelial and inducible nitric oxide synthase knockout (eNOS-/- and iNOS-/-) mice were subjected to 30-min left anterior descending coronary artery occlusion followed by reperfusion. Myocardial tissue oxygenation was monitored with electron paramagnetic resonance oximetry. Protein expressions of TGF-β1, receptor-activated small mothers against decapentaplegic homolog (Smad), p21 and α-smooth muscle actin (α-SMA) were measured with enzyme-linked immunosorbent assay (ELISA), Western immunoblotting, and immunohistochemical staining. Key findings There was a hyperoxic state in the post-ischemic myocardial tissue. Protein expressions of total and active TGF-β1, p-Smad2/3 over t-Smad2/3 ratio, p21, and α-SMA were significantly increased in WT mice compared to Sham control. Knockout of eNOS or iNOS further increased protein expression of these signals. The expression of α-SMA was more abundant in the infarct of eNOS -/- and iNOS-/- mice than WT mice. A protein band indicating nitration of TGF-β type-II receptor (TGFβRII) was observed from WT heart. Carbogen (95% O2 plus 5% CO2) treatment increased the ratio of p-Smad2/t-Smad2, which was inhibited by 10006329 EUK (EUK134) and sodium nitroprusside (SNP). In conclusion, hyperoxia up-regulated and NO/ONOO- inhibited cardiac TGF-β1 signaling and myofibroblast trans-differentiation. Significance These findings may provide new insights in myocardial infarct healing and repair.
AB - Aims Following ischemic injury, myocardial healing and remodeling occur with characteristic myofibroblast trans-differentiation and scar formation. The current study tests the hypothesis that hyperoxia and nitric oxide (NO) regulate TGF-β1 signaling in the post-ischemic myocardium. Main methods C57BL/6 wild-type (WT), endothelial and inducible nitric oxide synthase knockout (eNOS-/- and iNOS-/-) mice were subjected to 30-min left anterior descending coronary artery occlusion followed by reperfusion. Myocardial tissue oxygenation was monitored with electron paramagnetic resonance oximetry. Protein expressions of TGF-β1, receptor-activated small mothers against decapentaplegic homolog (Smad), p21 and α-smooth muscle actin (α-SMA) were measured with enzyme-linked immunosorbent assay (ELISA), Western immunoblotting, and immunohistochemical staining. Key findings There was a hyperoxic state in the post-ischemic myocardial tissue. Protein expressions of total and active TGF-β1, p-Smad2/3 over t-Smad2/3 ratio, p21, and α-SMA were significantly increased in WT mice compared to Sham control. Knockout of eNOS or iNOS further increased protein expression of these signals. The expression of α-SMA was more abundant in the infarct of eNOS -/- and iNOS-/- mice than WT mice. A protein band indicating nitration of TGF-β type-II receptor (TGFβRII) was observed from WT heart. Carbogen (95% O2 plus 5% CO2) treatment increased the ratio of p-Smad2/t-Smad2, which was inhibited by 10006329 EUK (EUK134) and sodium nitroprusside (SNP). In conclusion, hyperoxia up-regulated and NO/ONOO- inhibited cardiac TGF-β1 signaling and myofibroblast trans-differentiation. Significance These findings may provide new insights in myocardial infarct healing and repair.
KW - Fibrosis
KW - Hyperoxia
KW - Ischemia reperfusion injury
KW - Nitric oxide
KW - Oximetry
UR - https://www.scopus.com/pages/publications/84875409959
U2 - 10.1016/j.lfs.2013.01.018
DO - 10.1016/j.lfs.2013.01.018
M3 - Article
C2 - 23352974
AN - SCOPUS:84875409959
SN - 0024-3205
VL - 92
SP - 547
EP - 554
JO - Life Sciences
JF - Life Sciences
IS - 10
ER -