A single systemic injection of AAV9-hIGFBP2 prevents left ventricular hypertrophy and dysfunction in metabolic syndrome

Aims Metabolic syndrome (MetS) is a known risk factor for cardiovascular events. It is characterized by central obesity plus any two of dyslipidemia, insulin resistance, and hypertension. Obese and diabetic patients with MetS have low plasma insulin-like growth factor binding protein 2 (IGFBP2). Our first aim was to investigate IGFBP2 cardiac expression in MetS patients and in a mice model of MetS. The second aim was to assess if gene therapy with adeno-associated virus 9 carrying human IGFBP2 (AAV9-hIGFBP2) could reduce MetS associated left ventricular hypertrophy in mice. Methods and results We measured plasma IGFBP2 by ELISA and cardiac mRNA IGFBP2 expression in MetS patients by RT-qPCR. Both plasma levels and heart expression of IGFBP2 were decreased in patients with MetS vs. control patients. Further, in a C57BL/6J mouse model of diet-induced MetS, found similar left ventricular mRNA IGFBP2 expression. Finally, we demonstrated for the first time that in MetS mice with decreased cardiac IGFBP2 mRNA levels, human IGFBP2 can be induced by a single AAV9-hIGFBP2 injection, and that the increased IGFBP2 prevents left ventricle wall thickening, hypertrophy and dysfunction. Conclusion Human plasma and cardiac IGFBP2 are decreased in MetS patients. In mice, restoration of cardiac IGFBP2 expression level prevents MetS associated left ventricular dysfunction and hypertrophy. These clinical and animal data suggest that IGFBP2 is a new cardiac marker and therapeutic target in MetS to prevent heart remodeling consistent with heart failure.