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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 Ca2+-activated K+ current (BKCa), transient outward K+ current (Ito) and inwardly rectifying K+ current (IKir) were found in human atrial fibroblasts. Current density of BKCa (IC50 = 69.4 μM; n = 6), Ito (IC50 = 55.1 μM; n = 6) and IKir (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 Ito), but not KCa1.1 (encode BKCa) and Kir2.1 (encode IKir). 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.
Highlights
Cardiac fibroblasts are fundamentally involved in cardiac remodelling in normal ageing heart [1] and in damaged myocardium [2]
Aberrant proliferation of fibroblasts and their transformation to myofibroblasts is a hallmark of cardiac fibrosis, which is characterized by excessive extracellular matrix built-up leading to loss of tissue compliance [3
Multiple ionic channels are reported to be expressed in human cardiac ventricular fibroblasts [15], ionic channels in our atrial fibroblasts were activated by depolarization voltage between À70 and +60 mV from a holding potential of À80 mV (0.2 Hz) to elicit total outward K+ currents
Summary
Cardiac fibroblasts are fundamentally involved in cardiac remodelling in normal ageing heart [1] and in damaged myocardium [2]. Aberrant proliferation of fibroblasts and their transformation to myofibroblasts is a hallmark of cardiac fibrosis, which is characterized by excessive extracellular matrix built-up leading to loss of tissue compliance [3, 4]. Because of their wide-ranging participation in myocardial pathophysiology, cardiac fibroblasts represent an attractive target in managing cardiac disorders, including cardiac hypertrophy, heart failure and arrhythmias [5]. Hydrogen sulphide (H2S) is an endogenously generated gaseous transmitter that has been reported to attenuate cardiac fibrosis [9].
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