Heme Oxygenase Gene Targeting to Adipocytes Attenuates Adiposity and Vascular Dysfunction in Mice Fed a High-Fat Diet
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We examined the hypothesis that adipocyte dysfunction in mice fed a high-fat (HF) diet can be prevented by lentiviral-mediated and adipocyte specific-targeting delivery of the human heme oxygenase-1 (aP2-HO-1). A bolus intracardial injection of aP2-HO-1 resulted in expression of human HO-1 for up to 9.5 months. Transduction of aP2-HO-1 increased human HO-1 expression in fat tissues without affecting murine HO-1. In mice fed a HF diet, aP2-HO-1 transduction attenuated the increases in body weight, blood glucose, blood pressure, and inflammatory cytokines, as well as the content of both visceral and subcutaneous fat. Transduction of aP2-HO-1 increased the numbers of adipocytes of small cell size ( P <0.05), insulin sensitivity ( P <0.05), adiponectin levels, as well as vascular relaxation to acetylcholine compared with HF mice administered the aP2-green fluorescent protein. Adipocytes of mice fed a HF diet expressed high levels of peroxisome proliferator activator receptor, aP2, C/EBP, and Wnt5b proteins and displayed marked increases in Peg1/Mesoderm specific transcript ( P <0.03). Transduction of aP2-HO-1 lowered the elevated levels of these proteins and increased Sonic hedgehog, Wnt10b, and β-catenin ( P <0.05). Inhibition of HO activity by administration of tin mesoporphyrin to HF-fed mice transduced with the aP2-HO-1 reversed the decrease in Peg1/Mesoderm-specific transcript, TNFα, and MCP-1 levels. Collectively, this novel study demonstrates that adipocyte-specific overexpression of HO-1 attenuates HF-mediated adiposity and vascular dysfunction; increases insulin sensitivity; and improves adipocyte function by increasing adiponectin, Shh, and WNT10b, and by decreasing inflammatory cytokines. These effects are reversed by the HO activity inhibitor, stannous mesoporphyrin.
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Multiple mechanisms, including sympathetic overdrive, inflammatory mediators, excessive reactive oxygen species production, and decreased nitric oxide bioactivity, may contribute to the deleterious effects of obesity on the vasculature.
“Multiple other mechanisms including sympathetic overdrive, inflammatory mediators, excessive reactive oxygen species production, decreased NO bioactivity may contribute to the deleterious effects of obesity on the vasculature (70;71;74;75).”
From Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis (2014) · cites this paper as [70]
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Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis
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- Authors
- Cao, J., Peterson, S. J., Sodhi, K., Vanella, L., Barbagallo, I., Rodella, L. F., Schwartzman, M. L., Abraham, N. G., & Kappas, A.
- Affiliations
- New York Medical College (US)
- ORCID
- Venue
- Hypertension
- Published
- 2012-08
- Volume
- 60
- Issue
- 2
- Pages
- 467-475
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- PMC
- PMC3423899
- OpenAlex
- W2140035060
- Cited by
- 94
- References
- 57
- Citations by year
- 2024: 2 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 13 · 2019: 11 · 2018: 12 · 2017: 10 · 2016: 7 · 2015: 11 · 2014: 6 · 2013: 10
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL034300, HL 34300, HL55601)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK056601, R01DK068134, DK-068134)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- heme oxygenase-1, adipocytes, high-fat diet, adiposity, vascular dysfunction, insulin sensitivity, adiponectin, Sonic hedgehog, Wnt10b, β-catenin, PEG1/MEST, adipocyte inflammation, tin mesoporphyrin, lentiviral gene delivery
- MeSH terms
- Animals, Arteries, Cells, Cultured, Disease Models, Animal, Humans, Metalloporphyrins, Mice, Inbred C57BL, Obesity, Proteins, Tumor Necrosis Factor-alpha, Lentivirus, Adipocytes, Chemokine CCL2, Adiposity, Wnt Proteins, beta Catenin, Mice, Heme Oxygenase-1, Diet, High-Fat
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