Adenosine A2b Receptor Effects On Post-Mi Remodeling And Cardiac Fibroblast Function

<p>Adenosine A_2B receptor (A_2BR) appear to contribute to chronic inflammation. This receptor is highly expressed in macrophages and cardiac fibroblasts, cells which play key roles in inflammation and healing following myocardial infarction (MI). A_2BR have been shown to induce collagen production and promote organ fibrosis, although the reports of A_2BR role on MI are limited and conflicting. The results of cardiac fibroblast (CF) studies however suggest that non-selective A_2BR stimulation inhibits collagen expression. The hypothesis of the present study was that deletion of A_2BR reduces adverse remodeling in post-MI, and selective activation of A_2BR increases WT murine CF collagen and pro-inflammatory cytokines production. </p> <p>In our in vivo studies, MI was induced by permanent coronary artery occlusion in male WT and A_2BR KO mice. Hearts were harvested at 5 or 28-day post-MI for semi quantitative RT-PCR assay or sectioned and stained for morphological and histological studies. In CF experments, effects of selective A_2BR (BAY 60-6583, BAY) and A_2AR (CGS-21680, CGS) agonists on signaling (10 min) and collagen expression (24 h) were assessed by western blots. Adenosine receptor expression and agonist effects (24 h) on pro-inflammatory cytokine expression were analyzed with semi-quantitative real time PCR.</p> <p> Mortality of total animals and 28-day infarct size did not differ between genotypes. A2BR expression was 2.7 fold greater in WT scar zone compared to remote zone. TNF-α and MMP-9 expressions in the scar zone and collagen 1 and 3 mRNA levels in the remote zone were much greater in 5-day WT group without any change in macrophage infiltration. A_2BR KO hearts had greater scar thickness and lower infarct expansion. Our results indicated that ablation of A_2BR significantly decreased collagen deposition in 28-day post-MI remote zone. We also found that this effect was not due to downregulation of myofibroblasts but related to decreased macrophage infiltration at 28-day. Our results from CF studies indicated that A_2BR gene expression was two-fold greater than A_2AR, which was comparable to angiotensin AT1R. The A_2BR agonist BAY and the A_2AR agonist CGS both increased ERK and CREB phosphorylation. BAY and CGS effects on signaling were blocked by deletion of A_2BR and A_2AR, respectively. TGFβ-induced increases in collagen-1 expression were not altered by adenosine receptor agonists; in contrast, selective A_2BR and A_2AR stimulation increased collagen-1 expression, effects which were blunted by MEK (U0126) and PKA (H89) inhibitors. BAY, but not CGS, increased IL-6 gene expression, but neither agonist showed an effect on IL-1β mRNA levels. </p> <p>Our findings that a large increase in expression of the pro-inflammatory A_2BR occurs in the WT scar zone, and that A_2BR deletion reducing adverse post-MI heart remodeling in both scar and remote zones, suggest a detrimental role for A_2BR in this chronic pathological process, which could be, at least partially, through the effects on CF collagen and pro-inflammatory cytokine production.</p>

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Open Access Dissertation

Discipline thesis:degree_discipline

Physiology

Year dc:date.available

2014

Author dc:creator

• Zhan, Enbo

Contributors dc:contributor

• Robert D. Lasley

• Adenosine A2B receptor
• adverse remodeling
• cardiac fibroblast
• collagen
• inflammation
• myocardial infarction
• Pharmacology
• Physiology

Repository record dc:identifier

https://digitalcommons.wayne.edu/oa_dissertations/1062

OAI identifier oai:identifier

oai:digitalcommons.wayne.edu:oa_dissertations-2061