The interstitial concentration of adenosine remains elevated following MI continuing well after the injured tissue has healed and a scar has formed. However, the impact of adenosine signaling during post-MI remodeling and chronic ischemic heart failure remains unknown. In other organs, the novel concept has emerged that adenosine becomes damaging if it remains persistently elevated in tissues by activating pathways that promote fibrosis. This has been observed in experimental animal models of chronic lung, liver, kidney, and skin diseas- es. While the mechanisms by which adenosine becomes damaging vary, it generally acts to promote exces- sive tissue repair via activation of the A2BAR. The A2BAR is a unique member of the AR family abundantly ex- pressed in macrophages linked to cellular activation and production of inflammatory/fibrogenic cytokines. To determine the contribution of adenosine signaling during post-MI remodeling, we examined the effect of genet- ic deletion or blockade of the A2BAR (ATL-801) in a mouse model of permanent coronary artery ligation. Our preliminary data show a marked reduction in fibrosis with loss of A2BAR signaling at 8 weeks post-MI, which was associated with reduced inflammatory/fibrogenic activity in heart tissue, less dysfunction, and improved compliance. Central hypothesis: Augmented production of adenosine persists following MI, which contributes to fibrosis, pathological remodeling, and heart failure via activation of the A2BAR subtype.
Aim #1 will define the role of A2BAR signaling during post-MI remodeling. We will test whether genetic deletion or inhibition of the A2BAR will slow the rate of fibrosis that develops in surviving myocardium following MI resulting in less dysfunc- tion and ultimately prolonged survival.
This aim will be accomplished using ATL-801, Adora2b-/- mice, as well as a new line of Adora2b mutant rats created by our lab.
Aim #2 : To delineate the mechanisms by which A2BAR signaling contributes to adverse post-MI remodeling. Utilizing a conditionally targeted mouse line lack- ing expression of the A2BAR in myeloid-derived cells, assessments of macrophage infiltration/activation, and molecular analyses of post-MI heart tissue, we will test the hypothesis that persistent exposure to adenosine following MI stimulates the production of inflammatory mediators from macrophages that causes chronic in- flammation, fibroblast activation, and fibrosis.
Aim #3 : To delineate the magnitude and consequences of en- hanced adenosine production during post-MI remodeling and ischemic heart failure. We will assess changes in the interstitial concentration of adenosine in the surviving myocardium during the course of post-MI remodel- ing. We hypothesize that the interstitial concentration of adenosine will increase progressively during late re- modeling as the heart fails and that its enzymatic removal with pegylated-adenosine deaminase therapy will be protective. Completion of this work is expected to identify adenosine as an important fibrogenic mediator in the heart that contributes to pathological remodeling following MI through its interaction with the A2BAR subtype, and potentially identify a novel target for therapeutic intervention for patients with ischemic heart disease.
Each year over 1 million Americans experience a new or recurrent myocardial infarction due to underlying cor- onary artery disease. Twenty five percent of those patients that survive will eventually develop clinical heart failure with an average 5-year survival rate of 50% from the time of symptom onset. Heart failure occurs be- cause the remaining muscle undergoes changes that reduce its ability to pump blood efficiently, a process that is called cardiac remodeling. This research project will investigate mechanisms of cardiac remodeling and po- tentially identify a new treatment approach to slow or prevent this process from occurring in patients that have survived a heart attack.
| Du, Lili; Gao, Zhan-Guo; Paoletta, Silvia et al. (2018) Species differences and mechanism of action of A3 adenosine receptor allosteric modulators. Purinergic Signal 14:59-71 |
| Duroux, Romain; Ciancetta, Antonella; Mannes, Philip et al. (2017) Bitopic fluorescent antagonists of the A2A adenosine receptor based on pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine functionalized congeners. Medchemcomm 8:1659-1667 |
