IGF1-PI3K-induced physiological cardiac hypertrophy: Implications for new heart failure therapies, biomarkers, and predicting cardiotoxicity

Abstract

Heart failure represents the end point of a variety of cardiovascular diseases. It is a growing health burden and a leading cause of death worldwide. To date, limited treatment options exist for the treatment of heart failure, but exercise has been well-established as one of the few safe and effective interventions, leading to improved outcomes in patients. However, a lack of patient adherence remains a significant barrier in the implementation of exercise-based therapy for the treatment of heart failure. The insulin-like growth factor 1 (IGF1)-phosphoinositide 3-kinase (PI3K) pathway has been recognized as perhaps the most critical pathway for mediating exercised-induced heart growth and protection. Here, we discuss how modulating activity of the IGF1-PI3K pathway may be a valuable approach for the development of therapies that mimic the protective effects of exercise on the heart. We outline some of the promising approaches being investigated that utilize PI3K-based therapy for the treatment of heart failure. We discuss the implications for cardiac pathology and cardiotoxicity that arise in a setting of reduced PI3K activity. Finally, we discuss the use of animal models of cardiac health and disease, and genetic mice with increased or decreased cardiac PI3K activity for the discovery of novel drug targets and biomarkers of cardiovascular disease.

Keywords: Cardiac protection; Cardiotoxicity; Exercise; Heart failure; IGF1; PI3K; Therapies.

Fig. 1

A schematic diagram displaying the impact of physical activity or exercise on the IGF1–PI3K–Akt signaling pathway and the downstream physiological outcomes in the heart. Following exercise, IGF1 binds to the IGF1R embedded in the plasma membrane of cardiomyocytes, allowing for binding of p85, the regulatory subunit of PI3Kα. Once bound, p85 recruits p110α, the catalytic subunit of PI3Kα, forming the fully activated form of PI3Kα. Activated PI3Kα catalyzes the phosphorylation of PIP₂ to PIP₃, which recruits AKT and PDK1 to the plasma membrane. Binding of Akt to PIP₃ causes a conformational change in Akt, exposing the phosphorylation sites S473 and T308. Phosphorylation of S473 by MTORC2 and T308 by PDK1 activates Akt allowing for numerous downstream protective physiological changes to the heart (via Akt dependent and Akt independent mechanisms). P within the blue circle signifies phosphorylation. Akt = protein kinase B; BTK = Bruton's tyrosine kinase; HER = human epidermal growth factor receptor; IGF1= insulin-like growth factor 1; IGF1R = insulin-like growth factor receptor; MTORC2 = mammalian target of rapamycin complex 2; NRG1= neuregulin 1; PDK1 = phosphoinositide-dependent kinase 1; PIP₂ = phosphatidylinositol 4,5-bisphosphate; PIP₃ = phosphatidylinositol (3,4,5)-trisphosphate; PI3K = phosphoinositide 3-kinase; S473 = serine 473; T308 = threonine 308.

Fig. 2

PI3K is a master regulator of growth. Class IA PI3K(Dp110) overexpression in the wings of drosophila results in enlarged wings while over expression of a mutated inactive PI3K (Dp110^D954A) results in smaller wings. Similarly, caPI3K in the hearts of mice results in enlarged hearts, while the presence of a truncated mutated dnPI3K with reduced PI3K activity results in smaller hearts. caPI3K = constitutive activation of PI3K; dnPI3K = dominant negative PI3K; IGF = insulin-like growth factor; PI3K = phosphoinositide 3-kinase; WT = wild type.

Fig. 3

A summary of current approaches for the failing heart and new promising approaches for improving function in the failing heart (e.g., gene therapy). Approaches are separated into 4 categories based on the type of intervention: environmental and dietary based interventions, approaches involving genetic manipulation, pharmacological interventions, and surgical interventions. Combining multiple approaches may be an optimal strategy to maximize therapeutic outcomes. ACE = angiotensin-converting enzyme; CABG = coronary artery bypass graft; LVAD = left ventricular assist device; miRNA = microRNA.

Fig. 4

Anticancer therapeutics with the potential to inhibit the PI3Kα pathway. Trastuzumab binds to the extracellular domain of HER2 and triggers mechanisms to downregulate downstream activity. Ibrutinib inhibits BTK expression and is a known regulator of the PI3K–Akt pathway. Custirsen acts to silence clusterin, of which its expression has been correlated with PI3K activity, and may disrupt downstream processes. The mechanisms of anticancer therapies that suppress tumor growth by targeting the PI3K–Akt pathway may simultaneously contribute to an increased susceptibility for the development of cardiac pathologies. Red lines indicate interventions that act to silence, inhibit, or downregulate protein expression. Akt = protein kinase B; BTK = Bruton's tyrosine kinase; HER (ErbB) = human epidermal growth factor receptor; IGF1= insulin-like growth factor 1; IGF1R = insulin-like growth factor receptor; NRG1= neuregulin 1; PI3K = phosphoinositide 3-kinase.

Fig. 5

Identifying molecular distinctions between the healthy and diseased heart. A simplified pipeline demonstrating the process of using sequencing technologies to identify candidate therapeutics and biomarkers of cardiac health and disease. Tissue is collected, pooled, and processed from healthy and diseased hearts. A molecule of interest (e.g., DNA, RNA, protein, lipid) is sequenced and profiled. Expression is compared between groups to identify specific candidates that are discordant for cardiac health, or techniques such as principal component analysis can be used to identify global changes between groups. caPI3K = constitutive activation of PI3K; dnPI3K = dominant negative PI3K; PI3K = phosphoinositide 3-kinase.