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

TY - JOUR

T1 - Heme oxygenase-1 suppresses a pro-inflammatory phenotype in monocytes and determines endothelial function and arterial hypertension in mice and humans

AU - Wenzel, Philip

AU - Rossmann, Heidi

AU - Müller, Christian

AU - Kossmann, Sabine

AU - Oelze, Matthias

AU - Schulz, Andreas

AU - Arnold, Natalie

AU - Simsek, Canan

AU - Lagrange, Jeremy

AU - Klemz, Roman

AU - Schönfelder, Tanja

AU - Brandt, Moritz

AU - Karbach, Susanne H

AU - Knorr, Maike

AU - Finger, Stefanie

AU - Neukirch, Carolin

AU - Häuser, Friederike

AU - Beutel, Manfred E

AU - Kröller-Schön, Swenja

AU - Schulz, Eberhard

AU - Schnabel, Renate B

AU - Lackner, Karl

AU - Wild, Philipp S

AU - Zeller, Tanja

AU - Daiber, Andreas

AU - Blankenberg, Stefan

AU - Münzel, Thomas

N1 - Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

PY - 2015/12/21

Y1 - 2015/12/21

N2 - 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.

AB - 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.

KW - Animals

KW - Cross-Sectional Studies

KW - Endothelium, Vascular/physiopathology

KW - Female

KW - Heme Oxygenase-1/deficiency

KW - Humans

KW - Hypertension/mortality

KW - Male

KW - Mice

KW - Monocytes/physiology

KW - Neutrophils/physiology

KW - Oxidative Stress/physiology

KW - Phenotype

KW - Polymorphism, Genetic

KW - RNA, Messenger/metabolism

U2 - 10.1093/eurheartj/ehv544

DO - 10.1093/eurheartj/ehv544

M3 - SCORING: Journal article

C2 - 26516175

VL - 36

SP - 3437

EP - 3446

JO - EUR HEART J

JF - EUR HEART J

SN - 0195-668X

IS - 48

ER -