In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Bezerra, F (Author) Other; Niemietz, C (Author) Other; Schmidt, HHJ (Author) Other; Zibert, A (Author) Other; Guo, SL (Author) Other; Monia, BP (Author) Other; Goncalves, P (Author) Other; Maria Joao Saraiva (Author) FMUP; Almeida, MR (Author) ICBAS

Journal

Title: International Journal Of Molecular Sciences

Vol. 22 No. 9

Final page: 9488

ISSN: 1661-6596

Publisher: MDPI

Indexing

ISI Web of Knowledge - 4 Citations

Scopus - 4 Citations

Other information

Authenticus ID: P-00V-BGG

DOI: 10.3390/ijms22179488

Abstract (EN): Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17