In:
American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 293, No. 3 ( 2007-09), p. H1571-H1580
Kurzfassung:
Emerging research suggests that oxidant-driven transcription of key cytokine/chemokine networks within the myocardium plays a crucial role in producing ischemia-reperfusion (I/R) injury. We recently showed that activation of hypoxia-inducible factor-1 (HIF-1) attenuated cardiac I/R injury. Diminished injury in these prior studies was associated with significant reductions in circulating interleukin-8 levels, suggesting that HIF-1 may play an important role in modulating postischemic cardiac inflammation. In the current study, we examined the role of HIF-1 activation in modulating proinflammatory chemokine [macrophage inflammatory protein (MIP)-2, cytokine-induced neutrophil chemoattractant factor (KC), and lipopolysaccharide-induced CXC chemokine (LIX)] and adhesion molecule [intercellular adhesion molecule (ICAM)-1] expression in murine cardiomyocytes in vitro (HL-1 cell line) and in intact murine hearts following in vivo I/R injury. Our results show that HIF-1 activation induced both pharmacologically by the prolyl hydroxylase inhibitor dimethyloxallyl glycine and via small-interfering RNA (siRNA)-mediated prolyl-4 hydroxylase-2 (P4HA2) gene silencing significantly attenuated tumor necrosis factor-α-induced chemokine (KC and LIX) and ICAM-1 expression in cardiomyocytes. In vivo, postischemic hearts obtained from animals receiving the P4HA2 siRNA (HIF-1 activation) exhibited significantly reduced CXC chemokine (MIP-2, KC, and LIX), CC chemokine (monocyte chemoattractant protein-1), and ICAM-1 expression when compared with postischemic hearts from either saline I/R controls or postischemic hearts from animals receiving a nontargeting control siRNA (no HIF-1 activation). Diminished chemokine and adhesion molecule expression in HIF-1-activated postischemic hearts was associated with significantly reduced polymorphonuclear leukocyte infiltration and myocardial infarct size ( 〉 60% reduction P4HA2 siRNA I/R vs. saline I/R, P 〈 0.001, n = 6). In conclusion, these results demonstrate for the first time that HIF-1 activation following infusion of siRNA to P4HA2 plays a key role in modulating I/R-associated cardiac inflammatory responses.
Materialart:
Online-Ressource
ISSN:
0363-6135
,
1522-1539
DOI:
10.1152/ajpheart.00291.2007
Sprache:
Englisch
Verlag:
American Physiological Society
Publikationsdatum:
2007
ZDB Id:
1477308-9
SSG:
12
