The cofilin phosphatase slingshot homolog 1 restrains angiotensin II-induced vascular hypertrophy and fibrosis in vivo

• Type of Material: Article
• Authors: Holly C. Williams, Emory University; Jing Ma, Atlanta Veterans Affairs Medical Center; Daiana Weiss, Emory University; Bernard Lassegue, Emory University; Roy Sutliff, Emory University; Alejandra San Martin Almeyda, Emory University
• Language: English
• Date: 2019-03-01
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018, United States & Canadian Academy of Pathology.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41374-018-0116-6
• Title of Journal or Parent Work: Laboratory Investigation
• ISSN: 0023-6837
• Volume: 99
• Issue: 3
• Start Page: 399
• End Page: 410
• Grant/Funding Information: Microscopy experiments were performed in the Microscopy in Medicine Core, supported by NIH grant P01 HL095070.; This study was supported by The National Heart, Lung and Blood Institute of the National Institutes of Health under awards HL095070 and HL113167.
• Keywords: INDUCED OSTEOPONTIN EXPRESSION; Science & Technology; LIM KINASE; KAPPA-B ACTIVATION; Life Sciences & Biomedicine; INDUCED HYPERTENSION; EXTRACELLULAR-MATRIX; Medicine, Research & Experimental; ACTIN CYTOSKELETON; Research & Experimental Medicine; TRANSFORMING GROWTH-FACTOR-BETA-1; Pathology; SMOOTH-MUSCLE-CELLS; FIBRONECTIN BIOSYNTHESIS; MECHANICAL STRETCH
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

The dual specificity phosphatase slingshot homolog 1 (SSH1) contributes to actin remodeling by dephosphorylating and activating the actin-severing protein cofilin. The reorganization of the actin cytoskeleton has been implicated in chronic hypertension and the subsequent mechano-adaptive rearrangement of vessel wall components. Therefore, using a novel Ssh1 −/− mouse model, we investigated the potential role of SSH1 in angiotensin II (Ang II)-induced hypertension, and vascular remodeling. We found that loss of SSH1 did not produce overt phenotypic changes and that baseline blood pressures as well as heart rates were comparable between Ssh1 +/+ and Ssh1 −/− mice. Although 14 days of Ang II treatment equally increased systolic blood pressure in both genotypes, histological assessment of aortic samples indicated that medial thickening was exacerbated by the loss of SSH1. Consequently, reverse-transcription quantitative PCR analysis of the transcripts from Ang II-infused animals confirmed increased aortic expression levels of fibronectin, and osteopontin in Ssh1 −/− when compared to wild-type mice. Mechanistically, our data suggest that fibrosis in SSH1-deficient mice occurs by a process that involves aberrant responses to Ang II-induced TGFβ1. Taken together, our work indicates that Ang II-dependent fibrotic gene expression and vascular remodeling, but not the Ang II-induced pressor response, are modulated by SSH1-mediated signaling pathways and SSH1 activity is protective against Ang II-induced remodeling in the vasculature.