Deletion of <i>Phd2</i> in Myeloid Lineage Attenuates Hypertensive Cardiovascular Remodeling

<jats:sec xml:lang="en"> <jats:title>Background</jats:title> <jats:p xml:lang="en"> Hypertension induces cardiovascular hypertrophy and fibrosis. Infiltrated macrophages are critically involved in this process. We recently reported that inhibition of prolyl hydroxylase domain protein 2 ( <jats:styled-content style="fixed-case">PHD</jats:styled-content> 2), which hydroxylates the proline residues of hypoxia‐inducible factor‐α ( <jats:styled-content style="fixed-case">HIF</jats:styled-content> ‐α) and thereby induces <jats:styled-content style="fixed-case">HIF</jats:styled-content> ‐α degradation, suppressed inflammatory responses in macrophages. We examined whether myeloid‐specific <jats:italic>Phd2</jats:italic> deletion affects hypertension‐induced cardiovascular remodeling. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Methods and Results</jats:title> <jats:p xml:lang="en"> Myeloid‐specific <jats:styled-content style="fixed-case">PHD</jats:styled-content> 2‐deficient mice (MyPHD2KO) were generated by crossing <jats:italic>Phd2</jats:italic> ‐floxed mice with LysM‐Cre transgenic mice, resulting in the accumulation of <jats:styled-content style="fixed-case">HIF</jats:styled-content> ‐1α and <jats:styled-content style="fixed-case">HIF</jats:styled-content> ‐2α in macrophage. Eight‐ to ten‐week‐old mice were given <jats:italic>N</jats:italic> <jats:sup>G</jats:sup> ‐nitro‐L‐arginine methyl ester (L‐ <jats:styled-content style="fixed-case">NAME</jats:styled-content> ), a nitric oxide synthase inhibitor, and Angiotensin II (Ang II) infusion. L‐ <jats:styled-content style="fixed-case">NAME</jats:styled-content> /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. <jats:italic>Transforming growth factor</jats:italic> ‐β and <jats:italic>collagen</jats:italic> 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‐ <jats:styled-content style="fixed-case">NAME</jats:styled-content> /Ang II treatment in control mice were not observed in MyPHD2KO mice. Administration of digoxin that inhibits <jats:styled-content style="fixed-case">HIF</jats:styled-content> ‐α synthesis to L‐ <jats:styled-content style="fixed-case">NAME</jats:styled-content> /Ang II‐treated MyPHD2KO mice reversed these beneficial features. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Conclusions</jats:title> <jats:p xml:lang="en"> <jats:italic>Phd2</jats:italic> deletion in myeloid lineage attenuates hypertensive cardiovascular hypertrophy and fibrosis, which may be mediated by decreased inflammation‐ and fibrosis‐associated gene expression in macrophages. <jats:styled-content style="fixed-case">PHD</jats:styled-content> 2 in myeloid lineage plays a critical role in hypertensive cardiovascular remodeling. </jats:p> </jats:sec>