Increased apoptosis and premature cellular ageing of the diabetic heart underpin the development of diabetic heart disease. The molecular mechanisms underlying these pathologies are still unclear. Here we determined the role of pro-senescence microRNA (miR)-34a in accelerating the ageing of the diabetic heart. RT-PCR analysis showed a significant increase in the level of circulating miR-34a from early stages in asymptomatic type-2 diabetic individuals compared to non-diabetic controls. We also observed significant upregulation of miR-34a in the type-2 human diabetic heart suggesting circulating miR-34a may be cardiac in origin. Moreover, western blot analysis identified marked downregulation of the pro-survival protein sirtuin 1 (SIRT1), a direct target of miR-34a. Analysis of cultured human adult cardiomyocytes exposed to high glucose and cardiac progenitor cells (CPCs) isolated from the diabetic heart confirmed significant upregulation of miR-34a and downregulation of SIRT1, associated with a marked increase in pro-apoptotic caspase-3/7 activity. Although therapeutic inhibition of miR-34a activity restored SIRT1 expression in both cardiomyocytes and CPCs, p53 expression was further upregulated in cardiomyocytes but conversely downregulated in CPCs. In spite of increased p53, miR-34a inhibition significantly reduced high glucose induced apoptotic cell death in cardiomyocytes. However, this effect was not observed in CPCs, which in fact showed reduced proliferation following miR-34a inhibition. Taken together, our results demonstrate upregulation of miR-34a in the diabetic heart and in the circulation from an early stage of the disease. However, inhibition of miR-34a activity has differential effects depending on the cell type, thereby warranting the need to eliminate off-target effects when introducing miR-based therapy.
Pharmacology, Toxicology and Pharmaceutical Science
3
5%
Agricultural and Biological Sciences
3
5%
Chemical Engineering
2
3%
Other
5
8%
Unknown
22
35%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 20. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 19 September 2019.
All research outputs
#1,793,169
of 24,631,014 outputs
Outputs from Cell Death & Differentiation
#187
of 3,119 outputs
Outputs of similar age
#41,237
of 452,737 outputs
Outputs of similar age from Cell Death & Differentiation
#8
of 61 outputs
Altmetric has tracked 24,631,014 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 92nd percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 3,119 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 9.5. This one has done particularly well, scoring higher than 94% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 452,737 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 90% of its contemporaries.
We're also able to compare this research output to 61 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 88% of its contemporaries.
