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.
Department of Cardiac Surgery, Heart Center Dresden, Technical University Dresden, Dresden, Germany. Electronic address: Wolfgang.Witt@tu-dresden.de.
Wolfgang
W
Witt
Department of Cardiac Surgery, Heart Center Dresden, Technical University Dresden, Dresden, Germany.
Petra
P
Büttner
Department of Cardiac Surgery, Heart Center Dresden, Technical University Dresden, Dresden, Germany.
Anett
A
Jannasch
Department of Cardiac Surgery, Heart Center Dresden, Technical University Dresden, Dresden, Germany.
Klaus
K
Matschke
Department of Cardiac Surgery, Heart Center Dresden, Technical University Dresden, Dresden, Germany.
Thomas
T
Waldow
D036002:ADP Ribose Transferases / Q000494:pharmacology; D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001021:Aortic Valve / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016718:Arachidonic Acid / Q000494:pharmacology*; D001905:Botulinum Toxins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005786:Gene Expression Regulation; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D026362:Serum Response Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D046509:Tissue Culture Techniques; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D000199:Actins; D047630:Depsipeptides; D026362:Serum Response Factor; D015534:Trans-Activators; C057531:jasplakinolide; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D001905:Botulinum Toxins; D020742:rhoA GTP-Binding Protein
Aortic valve; Arachidonic acid; Docosahexaenoic acid; Myocardin-related transcription factor; RhoA; Valvular interstitial cell