1Universitätsmedizin der Johannes Gutenberg-Universität Mainz Centrum für Thrombose und Hämostase Mainz, Deutschland; 2Universitätsmedizin der Johannes Gutenberg-Universität Mainz Labor für Molekulare Kardiologie Mainz, Deutschland; 3Universitätsmedizin der Johannes Gutenberg-Universität Mainz Zentrum für Kardiologie Mainz, Deutschland
Background: Systemic arterial Hypertension is a pervasive cardiovascular disorder with a multifaceted etiology. Angiotensin II (Ang II), a potent vasoconstrictor and key player in the renin-angiotensin-aldosterone system (RAAS) causes vascular dysfunction, inflammation, and tissue damage. Heme oxygenase-1 (HO-1) overexpression may confer antioxidant and anti-inflammatory properties in Ang II-induced hypertension through its action on heme catabolism, generating carbon monoxide (CO), ferritin and biliverdin/bilirubin by the action of biliverdin reductase A (BLVRA).
Methods and results: Male 9–12-weeks-old HO-1indxLySMCre/wt and LySMCre/wt mice were infused with AngII (1mgAngII/Day/Kg) for 7 days to induce hypertension and compared to sham treatment. Blood pressure monitoring by tail-cuff method, and endothelium-dependent vasodilator studies via organ chamber system using acetylcholine (ACh) in isolated aortic rings (~4 mm), revealed that overexpression of HO-1 in myeloid cells resulted in decreased systolic blood pressure and to restored endothelial function in AngII-infused HO-1indxLySMCre/wt mice compared to controls. Concurrently, increased BLVRA expression in the liver and elevated plasma bilirubin levels were detected by transcriptome analysis and high-performance liquid chromatography (HPLC), respectively. These findings were accompanied by a reduction in the expression of pro-inflammatory cytokines and cell adhesion molecules (CAMs) in the aorta, assessed using quantitative polymerase chain reaction. Bone marrow transplant experiments demonstrated that bone marrow from LysMcre mice in HO-1indxLySMCre/wt mice nullified the protective effect of HO-1, resulting in endothelial damage and increased blood pressure, potentially due to decreased liver BLVRA expression. Additionally, adeno-associated viral vector (AAV) transfection targeting BLVRA activity in the liver lead to an increase in oxidative stress and the blood neutrophils concentration, as assessed in whole blood by using oxidative burst method and blood count system respectively.
Conclusion: HO-1 overexpression in myeloid cells largely restores vascular homeostasis in AngII-induced hypertension. BLVRA expression and bilirubin levels downstream of HO-1 play pivotal roles in protecting against vascular damage by reducing oxidative stress and inflammation.