Introduction and Objective: Despite being a major contributor to reduced life expectancy in type 1 diabetes (T1D), cardiovascular disease (CVD) and T1D-associated cardiomyopathy remain poorly understood. Insulin-like growth factor binding protein-7 (IGFBP7), a member of the IGFBPs, was found elevated in serum of patients with heart failure and kidney disease. Clinical studies in patients with diabetes showed that a change in serum IGFBP7 > 50% individually mediated 22% of cardiac outcomes, pointing at a residual cardiovascular risk linked to IGFBP7-mediated injury and at IGFBP7 as a new druggable target. The aim of our study was to test if IGFBP7 blockade protects from CVD and diabetic cardiomyopathy in vitro and in vivo.Methods: A human IGFBP7 inhibitor was generated by phage display and tested in vitro in human cardiomyocytes. In vivo efficacy was evaluated in a murine model of ischemic heart disease (C57BL6/J mice) and in streptozotocin (STZ)-induced diabetic mice. Treatment effects were assessed by analyzing infarct size, cardiac dysfunction and fibrosis. IGFBP7 level was also measured in patients with T1D and CVD (n=30 vs. non-diabetic controls) and in treated/untreated mice.Results: Serum IGFBP7 was 2-fold higher in patients with T1D and CVD (p<0.001 vs. controls) and in diabetic mice with ischemic CVD. In vitro, inhibition of IGFBP7 protected cardiomyocytes from diabetes- and pressure overload-induced damage. In vivo, IGFBP7 blockade preserved cardiac function, reduced cardiac fibrosis and promoted tissue remodeling. This protective effect was associated with up to a 40% decrease in serum IGFBP7 level.Conclusion: IGFBP7 is actively involved in the onset/progression of CVD in T1D and contributes to T1D-cardiomyopathy. IGFBP7 blockade prevents cardiac dysfunction and promotes cardiac remodeling in vitro and in vivo. As treatments for CVD are lacking in T1D, IGFBP7 inhibition may represent a new approach to target the IGFBP7-mediated residual cardiovascular risk and improve cardiac outcomes in this patients’ population.
F. D’Addio: Other – Founder and consultant; Ended; Enthera srl. A. Petrazzuolo: None. E. Assi: None. A. Maestroni: None. V. Usuelli: None. M. Zocchi: None. G. Rossi: None. R. Fiorina: None. A. Gandolfi: None. V. Cimino: None. L. Bucciarelli: None. L. Montefusco: None. C. Loretelli: None. M. Ben Nasr: None. P. Fiorina: Board Member; Ended; Novo Nordisk, Amgen Inc., Bristol-Myers Squibb Company.
Source link
Leave a Reply