Pietro Ameri1, Marco Canepa2, Patrizia Fabbi3, Giovanna Leoncini3, Yuri Milaneschi4, Michele Mussap5, Majd AlGhatrif6, Manrico Balbi3, Francesca Viazzi3, Giovanni Murialdo3, Roberto Pontremoli3, Claudio Brunelli3, Luigi Ferrucci7. 1. Department of Internal Medicine, AOU-IRCCS San Martino-IST, University of Genova, Genova, Italy. Electronic address: pietroameri@unige.it. 2. Department of Internal Medicine, AOU-IRCCS San Martino-IST, University of Genova, Genova, Italy; Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA. 3. Department of Internal Medicine, AOU-IRCCS San Martino-IST, University of Genova, Genova, Italy. 4. Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA; Department of Psychiatry and EMGO Institute for Health and Care Research, VU University Medical Center/GGZ inGeest, Amsterdam, The Netherlands. 5. Department of Laboratory Medicine, AOU-IRCCS San Martino-IST, Genova, Italy. 6. Laboratory of Cardiovascular Sciences, Human Cardiovascular Studies Unit, National Institute on Aging, NIH, Baltimore, MD, USA. 7. Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA.
Abstract
OBJECTIVE: Experimental evidence indicates that circulating insulin-like growth factor-1 (IGF-1) counteracts vascular aging and atherosclerosis, for which increased carotid artery intima-media thickness (IMT) is a marker. Yet, IGF-1 concentrations have been inconsistently associated with carotid IMT in epidemiological studies. Since vitamin D is also implicated in vascular protection and affects IGF-1 biology, we hypothesized that it would influence the effect of IGF-1 on IMT. METHODS: The relationship between carotid IMT and fasting serum IGF-1 was examined across strata of 25-hydroxyvitamin D [25(OH)D] in 472 participants in the Baltimore Longitudinal Study of Aging (BLSA) with well-controlled blood pressure and in 165 treatment-naive patients with essential hypertension from the Microalbuminuria: A Genoa Investigation on Complications (MAGIC) study. Moreover, the interplay between vitamin D and IGF-1 was preliminarily explored in EA.hy926 endothelial cells. RESULTS: After adjusting for age, sex, BMI, renal function, smoking, systolic blood pressure, LDL-cholesterol, glycemia, antihypertensive or lipid-lowering therapy, season, parathyroid hormone, and vitamin D supplementation, IGF-1 was significantly and negatively associated with carotid IMT only within the lowest 25(OH)D quartile (range 6.8-26 ng/mL) of the BLSA (β -0.095, p = 0.03). Similarly, a significant negative correlation between IGF-1 and carotid IMT was found after full adjustment only in MAGIC patients with 25(OH)D concentrations below either the deficiency cut-off of 20 ng/mL (β -0.214, p = 0.02) or 26 ng/mL (β -0.174, p = 0.03). Vitamin D dose-dependently decreased hydrogen peroxide-induced endothelial cell oxidative stress and apoptosis, which were further inhibited by IGF in the presence of low, but not high vitamin D concentration. CONCLUSIONS: Circulating IGF-1 is vasoprotective primarily when vitamin D levels are low. Future studies should address the mechanisms of vitamin D/IGF-1 interaction.
OBJECTIVE: Experimental evidence indicates that circulating insulin-like growth factor-1 (IGF-1) counteracts vascular aging and atherosclerosis, for which increased carotid artery intima-media thickness (IMT) is a marker. Yet, IGF-1 concentrations have been inconsistently associated with carotid IMT in epidemiological studies. Since vitamin D is also implicated in vascular protection and affects IGF-1 biology, we hypothesized that it would influence the effect of IGF-1 on IMT. METHODS: The relationship between carotid IMT and fasting serum IGF-1 was examined across strata of 25-hydroxyvitamin D [25(OH)D] in 472 participants in the Baltimore Longitudinal Study of Aging (BLSA) with well-controlled blood pressure and in 165 treatment-naive patients with essential hypertension from the Microalbuminuria: A Genoa Investigation on Complications (MAGIC) study. Moreover, the interplay between vitamin D and IGF-1 was preliminarily explored in EA.hy926 endothelial cells. RESULTS: After adjusting for age, sex, BMI, renal function, smoking, systolic blood pressure, LDL-cholesterol, glycemia, antihypertensive or lipid-lowering therapy, season, parathyroid hormone, and vitamin D supplementation, IGF-1 was significantly and negatively associated with carotid IMT only within the lowest 25(OH)D quartile (range 6.8-26 ng/mL) of the BLSA (β -0.095, p = 0.03). Similarly, a significant negative correlation between IGF-1 and carotid IMT was found after full adjustment only in MAGIC patients with 25(OH)D concentrations below either the deficiency cut-off of 20 ng/mL (β -0.214, p = 0.02) or 26 ng/mL (β -0.174, p = 0.03). Vitamin D dose-dependently decreased hydrogen peroxide-induced endothelial cell oxidative stress and apoptosis, which were further inhibited by IGF in the presence of low, but not high vitamin D concentration. CONCLUSIONS: Circulating IGF-1 is vasoprotective primarily when vitamin D levels are low. Future studies should address the mechanisms of vitamin D/IGF-1 interaction.
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