Reversal of myofibroblastic activation by polyunsaturated fatty acids in valvular interstitial cells from aortic valves. Role of RhoA/G-actin/MRTF signalling

Valvular interstitial cells (VICs), the fibroblast-like cellular constituents of aortic heart valves, maintain structural integrity of valve tissue. Activation into contractile myofibroblasts occurs under pathological situations and under standard cell culture conditions of isolated VICs. Reversal of this phenotype switch would be of major importance in respect to fibrotic valve diseases. In this investigation, we found that exogenous polyunsaturated fatty acids (PUFAs) decreased contractility and expression of myofibroblastic markers like α-smooth muscle actin (αSMA) in cultured VICs from porcine aortic valves. The most active PUFAs, docosahexaenoic acid (DHA) and arachidonic acid (AA) reduced the level of active RhoA and increased the G/F-actin ratio. The G-actin-regulated nuclear translocation of myocardin-related transcription factors (MRTFs), co-activators of serum response factor, was also reduced by DHA and AA. The same effects were observed after blocking RhoA directly with C3 transferase. In addition, increased contractility after induction of actin polymerisation with jasplakinolide and concomitant expression of αSMA were ameliorated by active PUFAs. Furthermore, reduced αSMA expression under PUFA exposure was observed in valve tissue explants demonstrating physiological relevance. In conclusion, RhoA/G-actin/MRTF signalling is operative in VICs, and this pathway can be partially blocked by certain PUFAs whereby the activation into the myofibroblastic phenotype is reversed.