Deletion of Phd2 in Myeloid Lineage Attenuates Hypertensive Cardiovascular Remodeling

Abstract

BackgroundHypertension induces cardiovascular hypertrophy and fibrosis. Infiltrated macrophages are critically involved in this process. We recently reported that inhibition of prolyl hydroxylase domain protein 2 (PHD2), which hydroxylates the proline residues of hypoxia‐inducible factor‐α (HIF‐α) and thereby induces HIF‐α degradation, suppressed inflammatory responses in macrophages. We examined whether myeloid‐specific Phd2 deletion affects hypertension‐induced cardiovascular remodeling.Methods and ResultsMyeloid‐specific PHD2‐deficient mice (MyPHD2KO) were generated by crossing Phd2‐floxed mice with LysM‐Cre transgenic mice, resulting in the accumulation of HIF‐1α and HIF‐2α in macrophage. Eight‐ to ten‐week‐old mice were given NG‐nitro‐L‐arginine methyl ester (L‐NAME), a nitric oxide synthase inhibitor, and Angiotensin II (Ang II) infusion. L‐NAME/Ang II comparably increased systolic blood pressure in control and MyPHD2KO mice. However, MyPHD2KO mice showed less aortic medial and adventitial thickening, and macrophage infiltration. Cardiac interstitial fibrosis and myocyte hypertrophy were also significantly ameliorated in MyPHD2KO mice. Transforming growth factor‐β and collagen expression were decreased in the aorta and heart from MyPHD2KO mice. Echocardiographic analysis showed that left ventricular hypertrophy and reduced ejection fraction induced by L‐NAME/Ang II treatment in control mice were not observed in MyPHD2KO mice. Administration of digoxin that inhibits HIF‐α synthesis to L‐NAME/Ang II‐treated MyPHD2KO mice reversed these beneficial features.ConclusionsPhd2 deletion in myeloid lineage attenuates hypertensive cardiovascular hypertrophy and fibrosis, which may be mediated by decreased inflammation‐ and fibrosis‐associated gene expression in macrophages. PHD2 in myeloid lineage plays a critical role in hypertensive cardiovascular remodeling.

PHD2 Is a Regulator for Glycolytic Reprogramming in Macrophages

“…Both characteristic features were severely impaired in the PHD2-deficient RAW cell model as well as the primary BMDM used in our study. Impaired migration is in line with two previous studies analyzing the migratory capacity of PHD2-deficient peritoneal macrophages as well as shPHD2 RAW cells toward MCP-1 as a stimulus (19,20). Infiltrating inflammatory cells, including macrophages, play an important role in tissue remodeling after an insult.…”

“…Infiltrating inflammatory cells, including macrophages, play an important role in tissue remodeling after an insult. In line with this, LysMCre PHD2 flox/flox animals showed less macrophage infiltration in the aorta during hypertensive cardiovascular remodeling (19). This was associated with protection from hypertension-induced left ventricular hypertrophy and reduced ejection fraction.…”

Hypoxia-dependent regulation of inflammatory pathways in immune cells

“…While our understanding of the role of HIF hydroxylases in the regulation of immune cell function is far from complete, recent studies investigating individual HIF hydroxylase isoforms in discreet immune and epithelial cell subtypes have identified isoform-specific roles (80)(81)(82)(83)(84)(85)(86)(87)(88)(89). Notably, these phenotypes are not fully accounted for by downstream HIF-dependent effects, further supporting the existence of alternative hydroxylase-regulated pathways such as NF-κB in immune cells.…”

“…In macrophages, PHD2 loss or haplodeficiency alters M1/ M2 cell differentiation in an NF-κB-dependent manner (80,81), whereas PHD3 loss alters apoptosis and proinflammatory activity (82,83). In neutrophils, PHD3 regulates apoptosis, although this effect appears to be NF-κB independent (84).…”

Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

“…98,99 Macrophage-specific prolyl hydroxylase domain protein 2 knockout mice also exhibited attenuated cardiac hypertrophy, fibrosis, and contractile dysfunction after L-NAME/Ang II infusion. 100 Furthermore, macrophage-specific miRNA-155 knockout mice showed less severe cardiac hypertrophy and contractile dysfunction after pressure overload with milder myocardial inflammation. 101 Mechanistically, miRNA-155 promotes cardiac inflammation and hypertrophy by downregulating the expression of suppressor of cytokine signaling 1, a direct target of miRNA-155.…”