Heme oxygenase-1 suppresses a pro-inflammatory phenotype in monocytes and determines endothelial function and arterial hypertension in mice and humans

被引：80

作者：

Wenzel, Philip ^{[1
,2
,3
]}

Rossmann, Heidi ^{[4
]}

Mueller, Christian ^{[5
,6
]}

Kossmann, Sabine ^{[1
,2
]}

Oelze, Matthias ^{[1
]}

Schulz, Andreas ^{[1
]}

Arnold, Natalie ^{[1
]}

Simsek, Canan ^{[1
]}

Lagrange, Jeremy ^{[2
]}

Klemz, Roman ^{[7
]}

Schoenfelder, Tanja ^{[2
]}

Brandt, Moritz ^{[1
]}

Karbach, Susanne H. ^{[1
]}

Knorr, Maike ^{[1
]}

Finger, Stefanie ^{[2
]}

Neukirch, Carolin ^{[4
]}

Haeuser, Friederike ^{[4
]}

Beutel, Manfred E. ^{[8
]}

Kroeller-Schoen, Swenja ^{[1
]}

Schulz, Eberhard ^{[1
]}

Schnabel, Renate B. ^{[5
,6
]}

Lackner, Karl ^{[4
]}

Wild, Philipp S. ^{[1
,2
,3
]}

Zeller, Tanja ^{[5
,6
]}

Daiber, Andreas ^{[1
]}

Blankenberg, Stefan ^{[5
,6
]}

Muenzel, Thomas ^{[1
,3
]}

机构：

[1] Univ Med Ctr Mainz, Dept Med 2, D-55131 Mainz, Germany

[2] Univ Med Ctr Mainz, Ctr Thrombosis & Hemostasis Mainz, D-55131 Mainz, Germany

[3] Univ Med Ctr Mainz, German Ctr Cardiovasc Res DZHK, Partner Site RhineMain, D-55131 Mainz, Germany

[4] Univ Med Ctr Mainz, Dept Lab Med, D-55131 Mainz, Germany

[5] Univ Med Ctr Hamburg Eppendorf, Univ Heart Ctr, D-20246 Hamburg, Germany

[6] German Ctr Cardiovasc Res DZHK, Partner Site Hamburg Kiel Luebeck, Berlin, Germany

[7] Charite Univ Med Ctr Berlin, Lab Chronobiol, D-10115 Berlin, Germany

[8] Univ Med Ctr Mainz, Dept Psychosomat Med & Psychotherapy, D-55131 Mainz, Germany

来源：

EUROPEAN HEART JOURNAL | 2015年 / 36卷 / 48期

关键词：

Heme oxygenase-1; Angiotensin II; Hypertension/high blood pressure; Endothelial function; Population studies; II-INDUCED HYPERTENSION; ANGIOTENSIN-II; CARBON-MONOXIDE; MICROSATELLITE POLYMORPHISM; OXIDATIVE STRESS; DYSFUNCTION; EXPRESSION; INDUCTION; CELL; MACROPHAGES;

D O I：

10.1093/eurheartj/ehv544

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims Heme oxygenase-1 (HO-1) confers protection to the vasculature and suppresses inflammatory properties of monocytes and macrophages. It is unclear how HO-1 determines the extent of vascular dysfunction in mice and humans. Methods and results Decreased HO-1 activity and expression was paralleled by increased aortic expression and activity of the nicotinamide dinucleotide phosphate oxidase Nox2 in HO-1 deficient Hmox1(-/-) and Hmox1(+/-) compared with Hmox1(+/+) mice. When subjected to angiotensin II-infusion, streptozotocin-induced diabetes mellitus and aging, HO-1 deficient mice showed increased vascular dysfunction inversely correlated with HO activity. In a primary prevention population-based cohort, we assessed length polymorphisms of the HMOX1 promoter region and established a bipolar frequency pattern of allele length (long vs. short repeats) in 4937 individuals. Monocytic HMOX1 mRNA expression was positively correlated with flow-mediated dilation and inversely with CD14 mRNA expression indicating pro-inflammatory monocytes in 733 hypertensive individuals of this cohort. Hmox1(-/-) mice showed drastically increased expression of the chemokine receptor CCR2 in monocytes and the aorta. Angiotensin II-infused Hmox1(-/-) mice had amplified endothelial inflammation in vivo, significantly increased aortic infiltration of pro-inflammatory CD11b(+)Ly6C(hi) monocytes and Ly6G(+) neutrophils and were marked by Ly6C(hi) monocytosis in the circulation and an increased blood pressure response. Finally, individuals with unfavourable HMOX1 gene promoter length had increased prevalence of arterial hypertension and reduced cumulative survival after a median follow-up of 7.23 years. Conclusions Heme oxygenase-1 is a regulator of vascular function in hypertension via determining the phenotype of inflammatory circulating and infiltrating monocytes with possible implications for all-cause mortality.

引用

页码：3437 / 3446

页数：10

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