To identify novel interventions targeting favorable myocardial remodeling and preventing heart failure (HF) progression remains challenging. To tackle this problem, it is essential to identify stage-specific mechanisms involved in the transition to maladaptive heart remodeling along with the fundamental of complex CM biology and cellular crosstalk. Insulin-like growth factor binding proteins (IGFBPs) are increasingly recognized as important factors understanding the pathogenesis and severity of cardiovascular disease. In this study, we focused on the potential role of IGFBP-5 as cardiac- and disease-stage-specific novel biomarker and modulator of cellular remodeling in (HF) development.

We explored the molecular networks triggered by β-catenin/TCF7L2 activation, typically observed in the diseased heart. Two independent screenings (Mouse Gene array and deep RNA-sequencing) showed upregulation of Igfbp-5 in hearts of a mouse model with b-catenin gain-of-function (GOF) in cardiomyocytes (CM), mimicking molecular and functional (HF) features. In the normal adult heart, Igfbp-5 was detected very low, which became significantly elevated upon hypertrophic-induced remodeling via transaortic constriction (TAC) between 2-8 weeks post-TAC, coincidently with a significant reduction of heart function and increase chamber dilation as indicated by echocardiography parameters (N≥5). In both models, GOF and TAC, IGFBP-5 upregulation was originated in CMs and detected increased in plasma obtained from these mice, suggesting an endocrine function of the heart. Supporting a conserved role, a significant upregulation of IGFBP-5 was also observed from healthy control to compensated hypertrophy and even more to (HF) in human heart biopsies and patients with severe aortic stenosis (AS) subjected to (TAVI) (N≥5/ per group). Accordingly, IGFBP-5 was increased in serum from these patients. IGFBP-5 levels normalized after intervention (6 months post-TAVI). Overexpression of IGFBP-5 in CM in vivo via adeno-associated virus serotype 9 (AAV9) resulted in serum elevation and activation of vascular fate processes. We also showed preliminary in vitro and in vivo evidences that IGFBP-5 have a paracrine action affecting non-CM cell fate including vascular cells. We identified IGF-dependent and independent mechanisms of action of IGFBP-5. Using enzymatically inactive CRISPR/(d)Cas9 overexpression system, along with specific guide RNA directed to IGFBP-5 promoter in mouse in vivo and human induced pluripotent stem cells (iPCS)-derived CM, we observed increased expression of IGFBP-5 not only at the transcript level but also secreted, which is further investigate to elucidate the pathophysiological role of IGFBP-5.

Combining mouse and human tissue analysis, we identified IGFBP-5 as an evolutionary conserved cardiokine, which can be detected during HF transition and may predict functional outcome. Mechanistically, our data support that dysregulation of CM transcriptional landscape in disease progression affects tissue remodeling in a non-autonomous manner, in which IGFBP-5 is involved. IGFBP-5 may trigger a signaling cellular network driving vascular remodeling in the transition to (HF).