Growth signalling and heart failure

Aging is a progressive and multi-factorial degenerative process affecting every organ system across the body.1 Thus, it is not surprising that age is the leading risk factor of disability and disease, including in the cardiovascular system. Several concepts and theories have been proposed throughout history in an effort to explain the complex process of aging, with the goal to develop anti-aging interventions that might be used to avert, attenuate or even reverse aging and related chronic disorders. Amongst these is the antagonistic pleiotropy theory of aging,2 which suggests that genes and molecular pathways with beneficial effects early in life might promote aging and related maladies at a later life stage. The insulin-like growth factor-1 (IGF1) signaling pathway is a good example. That is, although IGF1 plays an essential role in mediating cellular growth and metabolism, it also regulates the rate of aging across species.3 Thus, IGF1 signaling might promote aging by diverting limited cellular resources away from maintenance mechanisms – which are essential for repairing the damage accruing with advancing age – towards growth. In fact, IGF1 signaling was shown to exert a biphasic effects in the murine heart during the course of life. Transgenic mice with cardiomyocyte-specific IGF1 receptor overexpression show superior cardiac function at a young age, but display accentuated signs of cardiac aging and reduced longevity later in life, suggesting that cardiac IGF1 inhibition in the elderly might be beneficial.4 That said, the therapeutic potential of this pathway, especially in cardiovascular medicine, remains to be harnessed, as targeting IGF1 signaling in specific organs and tissues remains a challenge.

Towards this end, Zhang et al. published a recent paper examining the role of IGF-binding protein 7 (IGFBP7),5 which can regulate the availability and receptor-binding affinity of insulin-like growth factors, like IGF1. As to be expected,6 the authors found IGFBP7 to be overexpressed in the blood and hearts of patients with heart failure.5 To determine whether IGFBP7 upregulation is a bystander or a causal factor in the pathogenesis of heart failure, the authors turned to mice subjected transverse aortic constriction (TAC), a model of pressure overload-induced heart failure. Employing different strategies to attenuate IGFBP7 levels in these mice, including genetic IGFBP7 knockout, cardiomyocyte-targeted IGFBP7 knockdown and monoclonal antibody-mediated IGFBP7 neutralization, effectively improved cardiac function and structure. Surprisingly, reducing IGFBP7 did not activate, but rather suppressed IGF1 signaling, as indicated by reduced IGF1 levels and phosphorylation of its receptor and downstream effector AKT. Further supporting this notion, IGFBP7 deficiency led to reduced cardiac mass, both at baseline and in response to TAC. Mechanistically, it appears that IGFBP7 promotes cardiac senescence, inflammation and adverse fibrotic remodeling through IGF1-mediated suppression of FOXO3a, a pro-longevity factor known to induce autophagy, facilitate DNA repair and oxidative stress resistance. Notably, IGFBP7 appears to function as an adaptor protein that binds to and inhibits IGF1 receptor signaling, as deleting the N-terminal IGFBP motif attenuated IGFBP7 binding with the receptor and subsequent activation of AKT. These data are of major significance because they do not only support the prognostic value of IGFBP7 in heart failure, but also the therapeutic utility of the IGF1/IGFBP7 axis. Thus, targeting IGFBP7 might offer a more refined and measured approach to attenuate IGF1 signaling and, thus, might reduce off-target adverse effects typically associated with complete inhibition of the pathway.