Although the second messenger cyclic AMP (cAMP) is physiologically beneficial in the heart, it largely contributes to cardiac disease progression when dysregulated. Current evidence suggests that cAMP is produced within mitochondria. However, mitochondrial cAMP signaling and its involvement in cardiac pathophysiology are far from being understood.
To investigate the role of mitochondrial exchange protein directly activated by cAMP 1 (MitEpac1) in ischemia/reperfusion (I/R) injury.
We show that Epac1 genetic ablation (Epac1(-/-)) protects against experimental myocardial I/R injury with reduced infarct size and cardiomyocyte apoptosis. As observed in vivo, Epac1 inhibition prevents hypoxia/reoxygenation (HX+R)- induced adult cardiomyocyte apoptosis. Interestingly, a deleted form of Epac1 in its mitochondrial-targeting sequence protects against HX+R- induced cell death. Mechanistically, Epac1 favors Ca(2+) exchange between the endoplasmic reticulum and the mitochondrion, by increasing interaction with a macromolecular complex composed of the voltage-dependent anion channel 1 (VDAC1), the chaperone glucose-regulated protein 75 (GRP75), and the inositol-1,4,5-triphosphate receptor 1 (IP3R1) leading to mitochondrial Ca(2+) overload and opening of the mitochondrial permeability transition pore (MPTP). In addition, our findings demonstrate that MitEpac1 inhibits isocitrate dehydrogenase 2 (IDH2) via the mitochondrial recruitment of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), which decreases nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) synthesis, thereby reducing the antioxidant capabilities of the cardiomyocyte.
Our results reveal the existence, within mitochondria, of different cAMP-Epac1 microdomains that control myocardial cell death. In addition, our findings suggest Epac1 as a promising target for the treatment of ischemia- induced myocardial damage.
Pharmacology, Toxicology and Pharmaceutical Science
7
9%
Agricultural and Biological Sciences
7
9%
Neuroscience
2
3%
Other
4
5%
Unknown
27
36%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 4. 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 17 June 2021.
All research outputs
#10,173,233
of 31,634,113 outputs
Outputs from Circulation Research
#4,164
of 8,799 outputs
Outputs of similar age
#143,158
of 444,789 outputs
Outputs of similar age from Circulation Research
#66
of 116 outputs
Altmetric has tracked 31,634,113 research outputs across all sources so far. This one has received more attention than most of these and is in the 67th percentile.
So far Altmetric has tracked 8,799 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 12.5. This one has gotten more attention than average, scoring higher than 52% 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 444,789 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 67% of its contemporaries.
We're also able to compare this research output to 116 others from the same source and published within six weeks on either side of this one. This one is in the 41st percentile – i.e., 41% of its contemporaries scored the same or lower than it.
