Abstract 98: Myeloid-Specific Deletion of Prolyl Hydroxylase Domain Protein 2 Attenuates Hypertensive Cardiovascular Remodeling

Abstract

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. HIF-1α and 2α proteins were accumulated and mRNA expression of TNFα, IL-6 and IL-1β, M1 macrophage markers, and TGF-β and connective tissue growth factor (CTGF) expression were significantly decreased in peritoneal macrophages from MyPHD2KO mice compared with those from control mice. PHD2-deficient macrophage showed attenuated migration toward MCP-1. 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. Cardiac interstitial fibrosis (3.4±0.4 vs. 2.3±0.4%, p<0.05), macrophage infiltration and cardiac hypertrophy induced by L-NAEM/AngII were ameliorated in MyPHD2KO mice. Echocardiography revealed that treatment with L-NAME/AngII induced left ventricular hypertrophy and reduction of ejection fraction in control mice, which were not observed in MyPHD2KO mice. L-NAME/AngII-induced expression of TGF-β, CTGF, and Collagen I was decreased in the heart of MyPHD2KO mice. Conclusions: Myeloid specific PHD2 deletion attenuates cardiac hypertrophy and fibrosis induced by L-NAME/AngII, 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.