Cardioprotective role of APIP in myocardial infarction through ADORA2B

Abstract

In ischemic human hearts, the induction of adenosine receptor A2B (ADORA2B) is associated with cardioprotection against ischemic heart damage, but the mechanism underlying this association remains unclear. Apaf-1-interacting protein ( APIP) and ADORA2B transcript levels in human hearts are substantially higher in patients with heart failure than in controls. Interestingly, the APIP and ADORA2B mRNA levels are highly correlated with each other ( R = 0.912). APIP expression was significantly increased in primary neonatal cardiomyocytes under hypoxic conditions and this induction reduced myocardial cell death via the activation of the AKT-HIF1α pathway. Accordingly, infarct sizes of APIP transgenic mice after left anterior descending artery ligation were significantly reduced compared to those of wild-type mice. Strikingly, knockdown of APIP expression impaired the cytoprotective effects of ADORA2B during hypoxic damage. Immunoprecipitation and proximity ligation assays revealed that APIP interacts with ADORA2B, leading to the stabilization of both proteins by interfering with lysosomal degradation, and to the activation of the downstream PKA-CREB signaling pathways. ADORA2B levels in the hearts of APIP Tg/Tg , APIP Tg/+ , and Apip +/- mice were proportionally downregulated. In addition, ADORA2B D296G derived from the rs200741295 polymorphism failed to bind to APIP and did not exert cardioprotective activity during hypoxia. Moreover, Adora2b D296G knock-in mice were more vulnerable than control mice to myocardial infarction and intentional increases in APIP levels overcame the defective protection of the ADORA2B SNP against ischemic injury. Collectively, APIP is crucial for cardioprotection against myocardial infarction by virtue of binding to and stabilizing ADORA2B, thereby dampening ischemic heart injury.

PTB domain and leucine zipper motif 1 (APPL1) inhibits myocardial ischemia/hypoxia-reperfusion injury via inactivation of apoptotic protease activating factor-1 (APAF-1)/Caspase9 signaling pathway

“…The APAF-1 inhibitor attenuated cardiomyocyte apoptosis via disturbing procaspase-9 recruitment by APAF-1 [ 15 ]. Moreover, APAF-1-interacting protein plays cardioprotective roles in myocardial infarction [ 35 ]. Subsequently, APAF1 inhibitor ZYZ-488 was used to further validate whether APAF-1/Caspase9 signaling pathway mediated the cardioprotective role of APPL1 in I/R injury.…”

Allele-specific expression analysis for complex genetic phenotypes applied to a unique dilated cardiomyopathy cohort

“…When looking at genes that showed differential imbalance between the autoimmunity related phenogroup 2 and the rest of the cohort, four out of the top five most significant hits were related to inflammatory processes like programmed cell death and autophagy (Supplementary Table 2) [20][21][22][23] . One of these genes, APIP, has been shown to carry out a cardioprotective role in the inflammatory process following myocardial infarction 20 . TFEB is a protein degradation promotor previously linked to autophagy and lysosomal related cardiac disorders 22 .…”

A2B Adenosine Receptor and Cancer

“…Thus, it is conceivable that in many cases the predominant A 2B AR coupling is through Gαi rather than Gαs. Many important A 2B AR functions from primary cells or tissues have recently been related to the PI3K-Akt and Ras-related protein (RAP)1B-EPAC pathways [59,60,61,62,63]. However, it has not been extensively explored whether those signaling molecules are actually downstream of A 2B AR-mediated Gαi or Gαs proteins.…”

“…The cAMP-EPAC pathway and ERK1/2 phosphorylation are known to be involved in A 2B AR-mediated proliferation of some endothelial cells [55,83]. Limm et al, [61] showed that PKC, but not cAMP or Ca 2+ , is involved in 5′-methylthioadenosine (2)-induced and A 2B AR-mediated melanoma cell proliferation. Forskolin can mimic adenosine-induced proliferation of MDA-MB-231 breast cancer cells, suggesting that Gs-cAMP signaling is involved, although it is not clear whether PKA or EPAC is the downstream mediator.…”