Role of MicroRNA-145 in DNA Damage Signalling and Senescence in Vascular Smooth Muscle Cells of Type 2 Diabetic Patients

Abstract

Increased cardiovascular morbidity and mortality in individuals with type 2 diabetes (T2DM) is a significant clinical problem. Despite advancements in achieving good glycaemic control, this patient population remains susceptible to macrovascular complications. We previously discovered that vascular smooth muscle cells (SMC) cultured from T2DM patients exhibit persistent phenotypic aberrancies distinct from those of individuals without a diagnosis of T2DM. Notably, persistently elevated expression levels of microRNA-145 co-exist with characteristics consistent with aging, DNA damage and senescence. We hypothesised that increased expression of microRNA-145 plays a functional role in DNA damage signalling and subsequent cellular senescence specifically in SMC cultured from the vasculature of T2DM patients. In this study, markers of DNA damage and senescence were unambiguously and permanently elevated in native T2DM versus non-diabetic (ND)-SMC. Exposure of ND cells to the DNA-damaging agent etoposide inflicted a senescent phenotype, increased expression of apical kinases of the DNA damage pathway and elevated expression levels of microRNA-145. Overexpression of microRNA-145 in ND-SMC revealed evidence of functional links between them; notably increased secretion of senescence-associated cytokines and chronic activation of stress-activated intracellular signalling pathways, particularly the mitogen-activated protein kinase, p38α. Exposure to conditioned media from microRNA-145 overexpressing cells resulted in chronic p38α signalling in naïve cells, evidencing a paracrine induction and reinforcement of cell senescence. We conclude that targeting of microRNA-145 may provide a route to novel interventions to eliminate DNA-damaged and senescent cells in the vasculature and to this end further detailed studies are warranted.

Differential Expression of ATM, NF-KB, PINK1 and Foxo3a in Radiation-Induced Basal Cell Carcinoma

“…miR-26a and miR-100a were described as enhancing tumor cell radio-sensitivity via targeting DNA repair proteins [ 89 , 90 ]. miR-145 is described as a regulator of the DDR pathway and cellular senescence in different cell types [ 91 , 92 ]. Downregulation of miR-145-5p was also reported in basal cell carcinoma [ 93 ].…”

miR-145, miR-92a and miR-375 Show Differential Expression in Serum from Patients with Diabetic Retinopathies

“…miR-145 has also been associated with a senescent phenotype of smooth muscle cells (SMC) derived from patients with T2DM. This senescent phenotype can lead to DNA damage, with further vascular dysfunction [ 34 ]. Therefore, miR-145 has the potential to become a clinically useful biomarker of vascular damage.…”

“…The metabolic pathways that were enriched were related to apoptosis, focal adhesion, adherens, and tight junction pathways. All these pathways are involved in pericyte loss, which is a fundamental event for the development of DR [ 27 , 34 , 35 ]. Afterward, we used the target genes of the three validated miRNAs as input for enrichment analysis.…”

Evaluation of miRNA-143 and miRNA-145 Expression and Their Association with Vitamin-D Status Among Obese and Non-Obese Type-2 Diabetic Patients

“… 25 In the context of T2DM macrovascular complications, these are linked with aberrant miRNA-145 expression to saphenous vein smooth muscle cell senescence. 26 Both miRNA-143 and miRNA-145 promote the transition of vascular smooth muscle cells to a dysfunctional phenotype associated with T2DM. 21 Obesity increases miRNA-143 expression, which inhibits insulin-stimulated AKT phosphorylation in the liver and adipose tissue of obese mice and suggests that miRNA-143 is involved in the development of T2DM.…”