MiR-29a Increase in Aging May Function as a Compensatory Mechanism Against Cardiac Fibrosis Through SERPINH1 Downregulation

Evelyn Gabriela Rusu-Nastase; Ana-Mihaela Lupan; Catalina Iolanda Marinescu; Carmen Alexandra Neculachi; Mihai Bogdan Preda; Alexandrina Burlacu

doi:10.3389/fcvm.2021.810241

MiR-29a Increase in Aging May Function as a Compensatory Mechanism Against Cardiac Fibrosis Through SERPINH1 Downregulation

Front Cardiovasc Med. 2022 Jan 18:8:810241. doi: 10.3389/fcvm.2021.810241. eCollection 2021.

Authors

Evelyn Gabriela Rusu-Nastase¹, Ana-Mihaela Lupan¹, Catalina Iolanda Marinescu¹, Carmen Alexandra Neculachi¹, Mihai Bogdan Preda¹, Alexandrina Burlacu¹

Affiliation

¹ Laboratory of Stem Cell Biology, Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania.

Abstract

Deregulation of microRNA (miRNA) profile has been reportedly linked to the aging process, which is a dominant risk factor for many pathologies. Among the miRNAs with documented roles in aging-related cardiac diseases, miR-18a, -21a, -22, and -29a were mainly associated with hypertrophy and/or fibrosis; however, their relationship to aging was not fully addressed before. The purpose of this paper was to evaluate the variations in the expression levels of these miRNAs in the aging process. To this aim, multiple organs were harvested from young (2-3-months-old), old (16-18-months-old), and very old (24-25-months-old) mice, and the abundance of the miRNAs was evaluated by quantitative real-time (RT)-PCR. Our studies demonstrated that miR-21a, miR-22, and miR-29a were upregulated in the aged heart. Among them, miR-29a was highly expressed in many other organs, i.e., the brain, the skeletal muscle, the pancreas, and the kidney, and its expression was further upregulated during the natural aging process. Western blot, immunofluorescence, and xCELLigence analyses concurrently indicated that overexpression of miR-29a in the muscle cells decreased the collagen levels as well as cell migration and proliferation. Computational prediction analysis and overexpression studies identified SERPINH1, a specific chaperone of procollagens, as a potential miR-29a target. Corroborating to this, significantly downregulated SERPINH1 levels were found in the skeletal muscle, the heart, the brain, the kidney, and the pancreas harvested from very old animals, thereby indicating the role of the miR-29a-SERPINH1 axis in the aging process. In vitro analysis of miR-29a effects on fibroblast and cardiac muscle cells pointed toward a protective role of miR-29a on aging-related fibrosis, by reducing cell migration and proliferation. In conclusion, our study indicates an adaptive increase of miR-29 in the natural aging process and suggests its role as a transcriptional repressor of SERPINH1, with a potential therapeutic value against adverse matrix remodeling and aging-associated tissue fibrosis.

Keywords: SERPINH1; aging; fibrosis; miR-29a; miRNA; prediction analysis.