Hydrogen sulphide suppresses human atrial fibroblast proliferation and transformation to myofibroblasts.
Cardiac fibroblasts are crucial in pathophysiology of the myocardium whereby their aberrant proliferation has significant impact on cardiac function. Hydrogen sulphide (H2S) is a gaseous modulator of potassium channels on cardiomyocytes and has been reported to attenuate cardiac fibrosis. Yet, the mechanism of H2S in modulating proliferation of cardiac fibroblasts remains poorly understood. We hypothesized that H2S inhibits proliferative response of atrial fibroblasts through modulation of potassium channels. Biophysical property of potassium channels in human atrial fibroblasts was examined by whole-cell patch clamp technique and their cellular proliferation in response to H2S was assessed by BrdU assay. Large conductance Ca(2+)-activated K(+) current (BK(Ca)), transient outward K(+) current (I(to)) and inwardly rectifying K(+) current (IK(ir)) were found in human atrial fibroblasts. Current density of BK(Ca) (IC50 = 69.4 μM; n = 6), I(to) (IC50 = 55.1 μM; n = 6) and IK(ir) (IC50 = 78.9 μM; n = 6) was significantly decreased (P < 0.05) by acute exposure to NaHS (a H2S donor) in atrial fibroblasts. Furthermore, NaHS (100-500 μM) inhibited fibroblast proliferation induced by transforming growth factor-β1 (TGF-β1; 1 ng/ml), Ang II (100 nM) or 20% FBS. Pre-conditioning of fibroblasts with NaHS decreased basal expression of Kv4.3 (encode I(to)), but not KCa1.1 (encode BK(Ca)) and Kir2.1 (encode IK(ir)). Furthermore, H2S significantly attenuated TGF-β1-stimulated Kv4.3 and α-smooth muscle actin expression, which coincided with its inhibition of TGF-β-induced myofibroblast transformation. Our results show that H2S attenuates atrial fibroblast proliferation via suppression of K(+) channel activity and moderates their differentiation towards myofibroblasts.
Research and Development Unit, National Heart Centre Singapore, Singapore, Singapore.
Jingwei
J
Sheng
Winston
W
Shim
Heming
H
Wei
Sze Yun
SY
Lim
Reginald
R
Liew
Tien Siang
TS
Lim
Boon Hean
BH
Ong
Yeow Leng
YL
Chua
Philip
P
Wong
D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects*; D017931:DNA Primers; D005347:Fibroblasts / Q000187:drug effects*; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D016133:Polymerase Chain Reaction
D017931:DNA Primers; D006862:Hydrogen Sulfide
atrial fibrosis; fibroblast; hydrogen sulphide; potassium channel