Increased IGF1 levels in relation to heart failure and cardiovascular mortality in an elderly population: impact of ACE inhibitors

Chisalita, Simona I.; Dahlström, Ulf; Arnqvist, Hans J.; Alehagen, Urban

doi:10.1530/eje-11-0584

Cited by 23 publications

(17 citation statements)

References 38 publications

(52 reference statements)

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“…26 High levels of IGF-1 have been associated with heart failure and increased cardiac mortality. 64,65 Thus, it is postulated that downregulation of Gab1 is a result of increased IGF-1. Alternatively, the loss of Gab1 may be due to increased degradation through the ubiquitin-proteasome system.…”

Section: Resultsmentioning

confidence: 99%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

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A vital step in the development of heart failure is the transition from compensatory cardiac hypertrophy to decompensated dilated cardiomyopathy (DCM) during cardiac remodeling under mechanical or pathological stress. However, the molecular mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we investigate whether Gab1, a scaffolding adaptor protein, protects against hemodynamic stress-induced DCM and heat failure. We first observed that the protein levels of Gab1 were markedly reduced in hearts from human patients with DCM and from mice with experimental viral myocarditis in which DCM developed. Next, we generated cardiac-specific Gab1 knockout mice (Gab1-cKO) and found that GabcKO mice developed DCM in hemodynamic stress-dependent and age-dependent manners. Under transverse aorta constriction (TAC), Gab1-cKO mice rapidly developed decompensated DCM and heart failure, whereas Gab1 wild-type littermates exhibited adaptive left ventricular hypertrophy without changes in cardiac function. Mechanistically, we showed that Gab1-cKO mouse hearts displayed severe mitochondrial damages and increased cardiomyocyte apoptosis. Loss of cardiac Gab1 in mice impaired Gab1 downstream MAPK signaling pathways in the heart under TAC. Gene profiles further revealed that ablation of Gab1 in heart disrupts the balance of anti-and pro-apoptotic genes in cardiomyocytes. These results demonstrate that cardiomyocyte Gab1 is a critical regulator of the compensatory cardiac response to aging and hemodynamic stress. These findings may provide new mechanistic insights and potential therapeutic target for DCM and heart failure. The progression of heart failure is associated with cardiac remodeling, the changes of cardiac structure and function in response to various stress conditions such as pressure overload-generated hemodynamic stress and agingassociated oxidative stress. 1 Under hemodynamic stress, the heart undergoes a stage of compensated hypertrophy and then progresses into decompensated dilated cardiomyopathy (DCM) and heart failure. 2 Cardiac hypertrophy is an adaptive, regulatory process, in which activation of cardiomyocyte survival pathways maintains cardiac homeostasis against external stress. During the transition from compensatory hypertrophy to DCM, cardiomyocyte death plays a critical role in development of heart failure. [3][4][5][6] However, the molecular mechanisms for controlling the balance of cell survival and cell death during cardiac remodeling remain poorly understood.The Grb2-associated binder 1 (Gab1) is a member of the insulin receptor substrate-like multi-substrate docking protein family and expressed in various types of cells, including cardiomyocytes. [7][8][9] It is a central mediator of growth factor receptor signaling. 10,11 Gab1 is phosphorylated by tyrosine kinases, and then phosphorylated Gab1 recruits and activates phosphatidylinositol 3-kinase (PI3K)/Akt and protein tyrosine phosphatase SHP2 (PTPN11)/mitogen-activated protein kinase (MAPK...

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Section: Resultsmentioning

confidence: 99%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

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“…Moreover, collected studies lacked data regarding antihypertensive therapy, which has been proved to increase both IGF-1 levels 61,73 and myocardial tissue IGF-1 signaling, 74 as well as the opposite. 75 Our interaction analyses, however, indicated no mediation of antihypertensive therapy on the BP/IGF-1 relationship.…”

Section: Discussionmentioning

confidence: 99%

Revisiting the Relationship Between Blood Pressure and Insulin-Like Growth Factor-1

et al. 2014

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Abstract-Conflicting evidence exists on the relationship between blood pressure (BP) and insulin-like growth factor-1 (IGF-1). We reviewed available articles and pooled extrapolated regression coefficients for the association between BP and total IGF-1 as reported in the literature and included additional data from 912 individuals from the general population. We identified 20 studies including 11 704 subjects. We also measured total IGF-1, insulin-like binding protein-3, and BP in 912 black and white men and women from South Africa (aged 20-70 years). When plotting positive and negative weighed regression coefficients (29 data points) against IGF-1, we found a significant positive relationship (r=0.31; P<0.001; n=11 704) intercepting the 0 point at 191 ng/mL IGF-1, suggesting an inverse BP/IGF-1 relationship in low IGF-1 conditions, and a positive relationship in overtly high IGF-1 conditions. In conclusion, our findings suggest that the relationship between BP and IGF-1 is dependent on, or related to, IGF-1 concentrations, as an expression of direct or reverse causality. Low IGF-1 bioavailability (associated with aging and vascular deterioration), resistance to IGF-1, and the complex interplay between IGF-1 and other vasoactive hormones could mask the vasoprotective functions of IGF-1 in cross-sectional studies or could modify their functions in prospective studies.

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“…By binding 99% of circulating IGF-I, IGFBPs act as a natural store, which prolongs IGF-I half-life and modulates its biological activity (2). Both low and high levels of circulating IGF-I have been reported to be associated with increased mortality (3)(4)(5)(6), whereas high IGF-1 levels have been related with cancer mortality (7).…”

Section: Introductionmentioning

confidence: 99%

Proinsulin and IGFBP-1 predicts mortality in an elderly population

Chisalita

Dahlström

Arnqvist

et al. 2014

International Journal of Cardiology

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Increased IGF1 levels in relation to heart failure and cardiovascular mortality in an elderly population: impact of ACE inhibitors

Cited by 23 publications

References 38 publications

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

Revisiting the Relationship Between Blood Pressure and Insulin-Like Growth Factor-1

Proinsulin and IGFBP-1 predicts mortality in an elderly population

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