Journal
VASCULAR PHARMACOLOGY
Volume 51, Issue 2-3, Pages 110-118Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vph.2009.05.007
Keywords
Ischemia-reperfusion; Myocardium; Prolyl hydroxylase; Unfolded protein response
Categories
Funding
- National Heart, Lung, and Blood Institute [HL-076423]
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Ischemia/reperfusion (I/R) unleashes cellular events that threaten organ survival. I/R affects endoplasmic reticulum (ER) integrity and initiates the unfolded protein response (UPR). The adaptive arm of the UPR attenuates ER stress by increasing expression of chaperones promoting proper protein folding. However, failure to resolve ER stress leads to apoptotis. We recently showed that prolyl hydroxylase inhibition (PHI) attenuated post-ischemic cardiac injury. We hypothesized that PHI attenuated myocardial I/R injury through modulation of the UPR. We show for the first time that PHI activates all three regulatory arms of the UPR in murine microvascular endothelial cells and in mouse hearts. Cardiac I/R activated expression of proapoptotic CHOP (2.8 fold, n = 3, p<0.01). PHI significantly decreased CHOP expression (50%, n = 3, p<0.05) in post-ischemic hearts. PHI also induced activating transcription factor 4 (3.5 fold, n = 3, p<0.001), glucose-regulated protein 78 (6 fold, n = 3, p<0.001) and ER degradation-enhancing alpha-mannosidase-like protein (2.8 fold, n = 3, p<0.001) expression in reperfusing hearts. Thus PHI resulted in significant reduction of apoptosis in post-ischemic myocardium. Our studies suggest that PHI induces protective ER stress proteins and attenuates post-ischemic myocardial damage by decreasing the pro-apoptotic components of the UPR. (C) 2009 Elsevier Inc. All rights reserved.
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