P525Adiponectin deficiency blunts hypoxia-induced homing capacity of circulating angiogenic cells

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Abstract

Introduction

Adiponectin deficiency results in increasedinflammation, myocardial cell death and adverse myocardial remodeling in thesetting of acute myocardial infarction (AMI). Adiponectin has been reported toenhance endothelial nitric oxide synthase (eNOS) activity in an AMPK/PI3K/AKTdependent-manner. Since eNOS deficiency is known to attenuate circulating angiogeniccell (CAC) mobilization and function, we investigated the effects ofadiponectin deficiency on CAC mobilization, homing and neovascularization inthe setting of AMI.

Methods & Results

AMI was induced in wild-type (WT) (n=10) and adiponectin knockout (Adipoq-/-) mice (n=7). Oneweek after AMI, bone marrow (BM) concentration and mobilization of Sca-1 + and Lin-Sca-1 + progenitor cells (PCs) were markedlyattenuated under Adipoq-/- conditions,as assessed by flow cytometry. The mRNA expression of HIF-1-dependentchemotactic factors, such as Cxcl12(p < 0.005) and Ccl5 (p < 0.025),and vascular adhesion molecules, such as Icam1(p=0.010) and Vcam1 (p < 0.014), wassignificantly lower in the infarction border zone of Adipoq-/- mice. Gene expression of thePI3K/AKT/eNOS pathway and the HIF-1 hypoxia signaling pathway turned out to behighly correlated in WT mice, a relation that wascompletely lost under Adipoq-/-conditions. Histologically, Adipoq-/-mice evidenced a decrease in neovascularization capacity in the infarctionborder zone (p < 0.001). Overall, capillary density waspositively correlated with Sca-1 + PC numbers in BM (p=0.01) andperipheral blood (PB) (p=0.005) and with the expression of the homing factors Cxcl12 (p=0.013), Icam1 (p=0.034) and Vcam1(p=0.014).

Conclusions

Adiponectin deficiency reduced the BM reserve andmobilization capacity of CACs, attenuated the expression of hypoxia-inducedchemokines and vascular adhesion molecules and impaired the neovascularizationcapacity one week after AMI. Our data evidence a close inter-relationshipbetween CAC mobilization, homing and neovascularization after AMI in Adipoq-/- conditions.

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