Abstract 13578: Myeloid Specific Deletion Of PHD2 Attenuates Hypertensive Cardiovascular Remodeling
Background:Hypertension induces cardiovascular hypertrophy and fibrosis. Infiltration of inflammatory cells including macrophages is critically involved in this process. We recently reported that inhibition of prolyl hydroxylase domain protein 2 (PHD2), which hydroxylates proline residue of hypoxia-inducible factor α (HIFα) and thereby induces HIFα degradation, suppressed inflammatory responses in macrophage. We examined whether myeloid specific PHD2 deletion affects hypertension-induced cardiovascular remodeling.
Methods and Results: Myeloid-specific PHD2-deficient mice (MyPHD2KO) were generated by crossing PHD2-floxed mice with LysM-Cre transgenic mice. Eight to 10 week-old mice were given L-NAME (30mg/kg), an eNOS inhibitor, dissolved in 0.9% NaCl in the drinking water for 14days. Angiotensin II (AngII, 0.8 mg/kg/day) was infused subcutaneously via an osmotic mini-pump for the last 7 days of the experiment. L-NAME/AngII comparably increased systolic blood pressure in control and MyPHD2KO mice. However, MyPHD2KO mice showed less aortic medial (0.061±0.003mm vs 0.045±0.003mm, p<0.01) and adventitial thickening (0.051±0.004mm vs 0.036±0.003mm, p<0.01). In comparison with control mice, macrophage infiltration and the expression of F4/80 mRNA were significantly alleviated (p<0.01) in the aorta of MyPHD2KO mice in association with reduced proliferating cell nuclear antigen-positive cells in adventitia. Cardiac interstitial fibrosis (3.4±0.4% vs 2.3±0.4%, p<0.05) was also ameliorated in MyPHD2KO mice. TGF-β, connective tissue growth factor (CTGF), Collagen I expression were decreased in aorta and heart from MyPHD2KO mice. HIF-1α and 2α proteins were accumulated and expression of TNFα, IL-6 and IL-1β, a classic M1 macrophage markers, and TGF-β and CTGF, a fibrosis-associated gene expression were significantly decreased in peritoneal macrophages from MyPHD2KO mice compared with those from control mice.
Conclusions: Myeloid specific PHD2 deletion attenuates hypertensive cardiovascular hypertrophy and fibrosis, which may be mediated by decreased inflammation- and fibrosis-associated gene expression in macrophage. PHD2 in myeloid lineage plays a critical role in hypertensive cardiovascular remodeling.
- © 2012 by American Heart Association, Inc.