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.
Highlights
The persistent increase in human longevity has stimulated the interest of scientists in understanding the fundamental mechanisms underlying natural aging, which is the dominant risk factor for many pathologies, including cardiovascular diseases [1]
To further explore the function of miR-29a increase in the old heart and the skeletal muscle, the protein levels of collagen I and III, two targets of this miRNA which are both under the direct control of SERPINH1, were determined in miR-29a-overexpressing HL-1 cells
The quantification of hydroxyproline in the cardiac ventricle lysates obtained from the young, old, and very old animals, as a measure to estimate total collagen levels, showed increased levels of collagens in the old animals (Figure 6C), a result that was not intriguingly, being in agreement with the fibrosis development in the aging heart. This data suggests that the increase in the miR-29a level, noticed in multiple organs in the old individuals, is an adaptive response of the organism to the increased fibrosis associated with the aging process
Summary
The persistent increase in human longevity has stimulated the interest of scientists in understanding the fundamental mechanisms underlying natural aging, which is the dominant risk factor for many pathologies, including cardiovascular diseases [1]. Aging is a progressive process characterized by gradual changes and alterations accumulated in the tissues and organs, which eventually results in the reduced ability of the organism to meet increased demands [2, 3]. Aging is associated with increased production of reactive oxygen species, which are known to induce damages in mitochondrial DNA and redox-sensitive mitochondrial proteins, and to promote mitochondrial dysfunction, leading to heart failure and other pathologies [7]. All these hallmarks are interwoven and promote the gradual loss of physiological integrity and cell function, and eventually lead to the death of the organism
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