Interaction between Insulin-Like Growth Factor-1 and Atherosclerosis and Vascular Aging

Higashi, Yusuke; Quevedo, Henry C.; Tiwari, Summit; Sukhanov, Sergiy; Shai, Shaw‐Yung; Anwar, Asif; Delafontaine, Patrick

doi:10.1159/000360571

Cited by 48 publications

(12 citation statements)

References 143 publications

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“…Our finding, that low levels of IGF-I relate to QTc prolongation and therefore higher sudden cardiac death risk, fits with several other known adverse cardiovascular effects of IGF-I deficiency, that include accelerated cardiovascular aging, reduced cardiac contractility, hypertrophy, hypertension, coronary disease and even atrial fibrillation (19,53,70). Conversely, normal IGF-I levels appear to be cardioprotective, by stimulating the release of vasodilatory nitric oxide, and by promoting cell proliferation and differentiation (46,59). In mice IGF-I receptor deficiency has been associated with cardiomyopathy and heart failure (53).…”

Section: Discussionsupporting

confidence: 79%

“…An imbalance in serum IGF-I levels has been associated with a variety of negative effects, in several body systems, including obesity, diabetes and atherosclerosis. Reduced levels of IGF-I increase risk of hypertension, inflammation and endothelial dysfunction as normal IGF-I levels were shown to be protective, stimulating the release of nitric oxide, a vasodilator, and promoting cell proliferation and differentiation (46,59). Quantitatively, IGF-II is the predominant circulating IGF, present in adults at a concentration up to three times that of IGF-I (as noted in our cohort).…”

Section: Discussionsupporting

confidence: 71%

“…As IGF-I fulfills important somatic growth function it reaches its highest levels during teenage years, with levels subsequently decreasing with age (16,17) in a highly variable and individual process that is related to fat mass (16), sex, diet and hormonal status. Among its various functions, IGF-I protects against inflammation, hypertension, endothelial and β-cell dysfunction (46,59,62), inhibits growth hormone hypersecretion and suppresses insulin secretion whilst enhancing insulin's action (63). An imbalance in serum IGF-I levels has been associated with obesity, diabetes and atherosclerosis (46,59).…”

Section: Discussionmentioning

confidence: 99%

“…Among its various functions, IGF-I protects against inflammation, hypertension, endothelial and β-cell dysfunction (46,59,62), inhibits growth hormone hypersecretion and suppresses insulin secretion whilst enhancing insulin's action (63). An imbalance in serum IGF-I levels has been associated with obesity, diabetes and atherosclerosis (46,59).…”

Section: Discussionmentioning

confidence: 99%

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Declining Levels and Bioavailability of IGF-I in Cardiovascular Aging Associate With QT Prolongation–Results From the 1946 British Birth Cohort

Charalambous

Moon

Holly

et al. 2022

Front. Cardiovasc. Med.

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BackgroundAs people age, circulating levels of insulin-like growth factors (IGFs) and IGF binding protein 3 (IGFBP-3) decline. In rat cardiomyocytes, IGF-I has been shown to regulate sarcolemmal potassium channel activity and late sodium current thus impacting cardiac repolarization and the heart rate-corrected QT (QTc). However, the relationship between IGFs and IGFBP-3 with the QTc interval in humans, is unknown.ObjectivesTo examine the association of IGFs and IGFBP-3 with QTc interval in an older age population-based cohort.MethodsParticipants were from the 1946 Medical Research Council (MRC) National Survey of Health and Development (NSHD) British birth cohort. Biomarkers from blood samples at age 53 and 60–64 years (y, exposures) included IGF-I/II, IGFBP-3, IGF-I/IGFBP-3 ratio and the change (Δ) in marker levels between the 60–64 and 53y sampled timepoints. QTc (outcome) was recorded from electrocardiograms at the 60–64y timepoint. Generalized linear multivariable models with adjustments for relevant demographic and clinical factors, were used for complete-cases and repeated after multiple imputation.ResultsOne thousand four hundred forty-eight participants were included (48.3% men; QTc mean 414 ms interquartile range 26 ms). Univariate analysis revealed an association between low IGF-I and IGF-I/IGFBP-3 ratio at 60–64y with QTc prolongation [respectively: β −0.30 ms/nmol/L, (95% confidence intervals −0.44, −0.17), p < 0.001; β−28.9 ms/unit (-41.93, −15.50), p < 0.001], but not with IGF-II or IGFBP-3. No association with QTc was found for IGF biomarkers sampled at 53y, however both ΔIGF-I and ΔIGF-I/IGFBP-3 ratio were negatively associated with QTc [β −0.04 ms/nmol/L (−0.08, −0.008), p = 0.019; β −2.44 ms/unit (-4.17, −0.67), p = 0.007] while ΔIGF-II and ΔIGFBP-3 showed no association. In fully adjusted complete case and imputed models (reporting latter) low IGF-I and IGF-I/IGFBP-3 ratio at 60–64y [β −0.21 ms/nmol/L (−0.39, −0.04), p = 0.017; β −20.14 ms/unit (−36.28, −3.99), p = 0.015], steeper decline in ΔIGF-I [β −0.05 ms/nmol/L/10 years (−0.10, −0.002), p = 0.042] and shallower rise in ΔIGF-I/IGFBP-3 ratio over a decade [β −2.16 ms/unit/10 years (−4.23, −0.09), p = 0.041], were all independently associated with QTc prolongation. Independent associations with QTc were also confirmed for other previously known covariates: female sex [β 9.65 ms (6.65, 12.65), p < 0.001], increased left ventricular mass [β 0.04 ms/g (0.02, 0.06), p < 0.001] and blood potassium levels [β −5.70 ms/mmol/L (−10.23, −1.18) p = 0.014].ConclusionOver a decade, in an older age population-based cohort, declining levels and bioavailability of IGF-I associate with prolongation of the QTc interval. As QTc prolongation associates with increased risk for sudden death even in apparently healthy people, further research into the antiarrhythmic effects of IGF-I on cardiomyocytes is warranted.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Declining Levels and Bioavailability of IGF-I in Cardiovascular Aging Associate With QT Prolongation–Results From the 1946 British Birth Cohort

Charalambous

Moon

Holly

et al. 2022

Front. Cardiovasc. Med.

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“…Divergent data support that chronic modulation of IGF-1 promotes arterial obstructive lesions ( Bayes-Genis et al, 2000 ; Higashi et al, 2014 ), since it induces vascular smooth muscle cell (VSMC) proliferation in vitro ( Pfeifle et al, 1987 ) and increased IGF-1 and IGF-1 receptor have been shown in human and rabbit atherosclerotic arteries ( Grant et al, 1996 ; Grant et al, 1999 ) compared with normal tissues ( Grant et al, 1999 ). Future studies should elucidate whether age-related IGF-1 deficiency is further exacerbated by age-related changes in vascular expression of IGF-1–binding proteins (BPs), IGF-1 receptors or alterations in signaling pathways activated by IGF-1 receptors and whether it increases atherosclerosis risk in men and women.…”

Section: Possible Mechanisms Whereby Sex Differences Impact the Vascu...mentioning

confidence: 99%

Vascular Aging in Rodent Models: Contrasting Mechanisms Driving the Female and Male Vascular Senescence

et al. 2021

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Increasing scientific interest has been directed to sex as a biological and decisive factor on several diseases. Several different mechanisms orchestrate vascular function, as well as vascular dysfunction in cardiovascular and metabolic diseases in males and females. Certain vascular sex differences are present throughout life, while others are more evident before the menopause, suggesting two important and correlated drivers: genetic and hormonal factors. With the increasing life expectancy and aging population, studies on aging-related diseases and aging-related physiological changes have steeply grown and, with them, the use of aging animal models. Mouse and rat models of aging, the most studied laboratory animals in aging research, exhibit sex differences in many systems and physiological functions, as well as sex differences in the aging process and aging-associated cardiovascular changes. In the present review, we introduce the most common aging and senescence-accelerated animal models and emphasize that sex is a biological variable that should be considered in aging studies. Sex differences in the cardiovascular system, with a focus on sex differences in aging-associated vascular alterations (endothelial dysfunction, remodeling and oxidative and inflammatory processes) in these animal models are reviewed and discussed.

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Mexican case report of a never‐treated Laron syndrome patient evolving to metabolic syndrome, type 2 diabetes, and stroke

Castilla‐Cortázar

Femat-Roldán

Rodríguez-Rivera

et al. 2017

Clinical Case Reports

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Interaction between Insulin-Like Growth Factor-1 and Atherosclerosis and Vascular Aging

Cited by 48 publications

References 143 publications

Declining Levels and Bioavailability of IGF-I in Cardiovascular Aging Associate With QT Prolongation–Results From the 1946 British Birth Cohort

Declining Levels and Bioavailability of IGF-I in Cardiovascular Aging Associate With QT Prolongation–Results From the 1946 British Birth Cohort

Vascular Aging in Rodent Models: Contrasting Mechanisms Driving the Female and Male Vascular Senescence

Mexican case report of a never‐treated Laron syndrome patient evolving to metabolic syndrome, type 2 diabetes, and stroke

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