MicroRNA-29a induces apoptosis via increasing the Bax:Bcl-2 ratio in dermal fibroblasts of patients with systemic sclerosis

Abstract

The most prominent feature of systemic sclerosis (SSc) and other diseases associated with fibrosis is the prolonged activation of fibroblasts not eliminated by apoptosis, hence characterized by accumulation of more extra cellular matrix (ECM). We tend to verify if microRNA-29a (miR-29a) as an anti-fibrotic factor could induce apoptosis in SSc fibroblasts. We did not detect apoptosis in SSc fibroblasts. We found that Bcl-2 expression was upregulated in SSc fibroblasts and the ratio of Bax:Bcl-2 in these cells was significantly lower (p = 0.02) compared to normal fibroblasts. Transfection of both SSc and transforming growth factor-β (TGF-β) stimulated fibroblasts by miR-29a mimic, significantly decreased the expression of two anti-apoptotic members of the Bcl-2 family, Bcl-2 (p = 0.0005, p = 0.01) and Bcl-XL (p = 0.0001, p = 0.006), resulted in enhanced Bax:Bcl-2 ratio and induced a high rate of apoptosis. Recently, miR-29 has been introduced as an anti-fibrotic factor with potential therapeutic effect on SSc. Until now, it has not been proposed whether there is a relationship between miR-29a and apoptosis in SSc. According to our results, it seems that miR-29a is a potent inducer of apoptosis in SSc fibroblasts and an attenuator of ECM production in these cells. MiR-29a disrupted the expression profiling of Bcl-2 family proteins (Bax, Bcl-2 and Bcl-XL) which is the central point of dynamic life-death rheostat in many apoptotic pathways. Furthermore, dermal fibroblasts from patients with SSc showed elevation in TNF-α mRNA levels, while restoration of miR-29a decreases TNF-α production in these cells. Although further molecular studies are necessary to investigate the underlying apoptotic pathways, the present findings suggest that anti-fibrotic and pro-apoptotic properties of miR-29a could provide novel benefits toward the development of fibroblast-specific anti-fibrotic therapies.

MicroRNA-29a Counteracts Synovitis in Knee Osteoarthritis Pathogenesis by Targeting VEGF

“…High fibrogenic activity in cell cultures after miR-29a knockdown also extrapolated the existence of abundant fibrotic matrices in synovial compartment in end-stage OA. Our analyses agreed with other studies demonstrating that the miR-29 family reduces TGF-β1 signaling exaggeration of fibrotic matrix deposition in fibroblast cultures from cardiac 33 , lung 34 , and systemic sclerotic tissues 35 . Current investigations indicated that miR-29a signaling exerted a protective function against excessive synovial remodeling.…”

Inhibition of MicroRNA‐21 induces apoptosis in dermal fibroblasts of patients with systemic sclerosis

“…reported similar results obtained in a TUNEL (TdT‐mediated dUTP nick‐end labeling) assay . Our recent study represented the first report to suggest that an miRNA (i.e. miR‐29a) restoration induces apoptosis in SSc fibroblasts.…”

DecreasedTRPM7inhibits activities and induces apoptosis of bladder cancer cells via ERK1/2 pathway

“…Proteins involved in cell cycle regulation, CCND1 and CDK2/4, were all reduced after the siTRPM7 treatment. Moreover, proteins involved in apoptosis were strongly altered, especially imbalance of the BAX/BCL2 ratio, which is involved in mitochondrial-dependent apoptosis [62, 63], and related proteins including cleaved-caspase 3 [64, 65] and Cytochrome C [66, 67], suggesting that TRPM7 deficiency could trigger a mitochondrial-mediated apoptosis. Importantly, as suggested by our microarray analysis, MAPK signaling pathway, a central regulator in the pathway network, could be altered by the affected calcium signaling pathway due to TRPM7 knockdown.…”