Introduction: Obesity or high fat diet (HF) are risk factors for the development of hypertension.
We examined the hypothesis that targeting the vascular system with human heme oxygenase -1 (HO-1) may attenuate both vascular and adipocyte dysfunction in vivo and in vitro.
Methods: Lentivirus (Lenti) construct expressing human HO-1 under the control of endothelium specific promoters VE-cadherin (VECAD-HO-1) and VECAD −GFP (control) were used to treat mice, using a bolus injection into the renal artery, and kept on a high fat diet for 26 weeks. Human HO-1 gene expression was sustained for 9 months. For in vitro studies, human EC were cultured with Lenti- VECAD-HO-1 and added to Lenti-VECAD-GFP or control. The conditioned media (CM) from ECs was harvested and 10% CM was added to adipogenic media to measure paracrine effect on adipogenesis in human Mesenchymal Stem Cells (MSCs) derived adipocytes. Signaling molecules were measured by western blot.
Results: Lentiviral transduction with VECAD-HO-1 construct attenuated the increase in blood pressure (from 149.9 ± 2.4 to 118 ± 2.0 mmHg, p<0.01) and prevented body weight gain by 39% (p<0.05) in obese mice and increased plasma adiponectin (from 2.9 ± 0.2 to 6.5 ± 0.1 μg/ml, p<0.05). CM derived from EC lenti HO-1 decreased adipogenesis compared to control (from 17.0 ± 0.2 to 10.2 ± 0.1, p<0.05) and resulted in an increase of β-catenin and Wnt but a decrease in PPARγ (p<0.05). These beneficial effects were reversed by treating the cell with SnMP, an inhibitor of HO activity (p<0.01). EC-HO-1 increased angiopoietin-1 (ANG-1), vascular endothelial growth factor A (VEGF), and platelet derived growth factor (PDGF)-AA,−BB (p<0.05). The addition of ANG-1 to adipogenic media resulted in the inhibition of adipogenesis (8.1 ± 0.1, p<0.01).
Conclusion: Targeting HO-1 to ECs resulted in the attenuation of blood pressure and the prevention of body weight gain resulting in increased ANG-1, PDGF, and VGEF levels and the reprogramming of MSCs derived adipocytes to produce healthy and smaller adipocytes with the release of adiponectin.