Abstract 252: Activated Fibroblast-specific Deletion of RhoA Reduces Cardiac Fibrosis Through Regulation of the Non-canonical p38-MAPK Signaling Pathway

• Published in: Circulation research 2019-08, Vol.125 (Suppl_1)
• Main Authors: Kaikkonen, Leena A, Sätzler, Valerie, Roy, Ashbeel, Contreras, Mauricio, Xu, Bing, Stroll, Stefanie, McCarthy, Jason, Molkentin, Jeffery D, Das, Saumya, Kontaridis, Maria
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/res.125.suppl_1.252

Abstract only Objective: Heart failure is a progressive disease characterized by cardiomyocyte (CM) loss, interstitial fibrosis, loss of ventricular compliance and chamber remodeling. Role of cardiac fibroblasts is implicated in the process, but specific molecular mechanisms regulating their function remain unclear. Previously, we showed that in mice, in response to stress, CM-specific deletion of RhoA, a Ras-related small G protein, accelerated cardiac dilation, with significant loss of contractile function, but it also significantly reduced cardiac fibrosis. Therefore, here, we focused on understanding the role of RhoA specifically in myofibroblast transformation and the fibrotic response. Results: We generated mice with activated fibroblast-specific deletion of RhoA using a tamoxifen (TMX) inducible periostin-cre promoter (RhoAfl/fl::PSTN Cre/+). 10-wk-old male RhoAfl/fl::PSTN Cre/+ or control mice were treated with angiotensin-phenylephrine (AngPE) or saline for 4 wk using osmotic minipumps and fed either with TMX or regular diet. Following TMX-AngPE treatment, the RhoAfl/fl::PSTN Cre/+ mice showed significantly decreased cardiac fibrosis, as compared to controls (0.9% vs. 3.2%, respectively). Moreover, while overall cardiac function following AngPE treatment was similar at 4 wk in all groups, hearts from the TMX-RhoAfl/fl::PSTN Cre/+ mice had significantly reduced septal thickness, as compared to controls. Expression of fetal genes, ANF, BNP, and β-MHC, as well as markers of fibrosis, including α-SMA and CTGF, were similarly induced in control and TMX-RhoAfl/fl::PSTN Cre/+ mice. However, TMX-RhoAfl/fl::PSTN Cre/+ mice had reduced expression of TGF-β1, thrombospondin-5 and Col1a2. Finally, RhoA deletion in activated fibroblasts did not affect the canonical TGFβ signaling pathway, as expected; instead, we found TMX-RhoAfl/fl::PSTN Cre/+ hearts had reduced non-canonical p38-MAPK signaling, suggestive of cellular-specific effects of RhoA regulation in the onset of cardiac disease and fibrosis. Conclusions: These data confirm the primacy of the RhoA pathway in the fibrotic response in vivo and identify potential novel downstream targets and possible therapeutic strategies for treatment of cardiac fibrosis and heart failure.