Abstract Background Arterial hypertension is a systemic cardiovascular disorder associated with detrimental effects orchestrated by Angiotensin II (AngII) in the renin-angiotensin-aldosterone system (RAAS). AngII causes vascular dysfunction, inflammation, and tissue damage. Increased expression of heme oxygenase-1 (HO-1) may confer antioxidant and anti-inflammatory protection in AngII-induced hypertension by catalyzing heme breakdown to carbon monoxide (CO) and biliverdin, which is reduced to bilirubin by the biliverdin reductase A (BLVRA), as well as indirectly by induction of ferritin through the release of iron. Methods and results Male9–12-weeks-old HO-1indxLySMCre/wt and LySMCre/wt control mice were infused with AngII (1mg AngII/day/kg) for 7 days to induce hypertension. Overexpression of HO-1 in myeloid cells resulted in decreased systolic blood pressure and restored endothelial function in AngII-infused HO-1indxLySMCre/wt mice compared to controls, as assessed by tail-cuff method and endothelium-dependent vasodilator studies. Transcriptome analysis and HPLC-measurements revealed increased BLVRA expression in the liver and elevated plasma bilirubin levels, in line with reduced expression of pro-inflammatory cytokines and cell adhesion molecules (CAMs) in the aorta, assessed by qPCR. Bone marrow transplantation experiments demonstrated that bone marrow from LysMCre/wt mice in HO-1indxLySMCre/wt mice nullified the protective effect of HO-1, causing endothelial damage and increased blood pressure, potentially due to decreased liver BLVRA expression and bilirubin concentration. In a mouse model of heart failure model induced by excess neurohormonal activation (unilateral nephrectomy, 4-weeks AngII and high salt), HO-1indxLysMCre/wt showed less cardiac remodeling and protection from left ventricular and renal dysfunction. Conclusion HO-1 overexpression in myeloid cells largely restores vascular homeostasis in AngII-induced hypertension and (hypertensive) heart failure in HO-1indxLyMCre/wt mice. BLVRA expression and bilirubin levels downstream of HO-1 play pivotal roles in protecting against vascular damage by reducing oxidative stress and inflammation.
Aluia et al. (Sat,) studied this question.