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Published on: June 3, 2018
Hydrogen sulphide suppresses human atrial fibroblast proliferation and transformation to myofibroblasts
Jingwei Sheng1, Winston Shim, Heming Wei
1Research and Development Unit, National Heart Centre Singapore, Singapore, Singapore.
Insights
Hydrogen sulfide (H2S) inhibits atrial fibroblast proliferation by suppressing potassium channel activity. This gas molecule also moderates fibroblast differentiation, offering potential therapeutic avenues for cardiac fibrosis.
Area of Science:
- Cardiovascular Biology
- Cell Physiology
- Molecular Medicine
Background:
- Cardiac fibroblasts are key players in myocardial pathophysiology, with aberrant proliferation significantly impacting cardiac function.
- Hydrogen sulfide (H2S) is known to modulate potassium channels and attenuate cardiac fibrosis, but its mechanism in fibroblast proliferation is unclear.
Purpose of the Study:
- To investigate the mechanism by which H2S modulates atrial fibroblast proliferation, hypothesizing inhibition via potassium channel modulation.
Main Methods:
- Whole-cell patch clamp electrophysiology to examine potassium channel biophysical properties in human atrial fibroblasts.
- BrdU assay to assess cellular proliferation in response to H2S.
- Western blotting to analyze protein expression (Kv4.3, KCa1.1, Kir2.1, α-smooth muscle actin).
Main Results:
- Human atrial fibroblasts exhibit BK(Ca), I(to), and IK(ir) currents.
- NaHS (H2S donor) significantly decreased the current density of BK(Ca), I(to), and IK(ir) in atrial fibroblasts.
- NaHS inhibited fibroblast proliferation induced by TGF-β1, Ang II, or FBS, and attenuated TGF-β1-stimulated Kv4.3 and α-smooth muscle actin expression.
Conclusions:
- H2S attenuates atrial fibroblast proliferation by suppressing potassium channel activity.
- H2S moderates atrial fibroblast differentiation into myofibroblasts, suggesting a role in mitigating cardiac fibrosis.
Abstract:
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.
