Molecular basis of physiological heart growth: fundamental concepts and new players

Abstract

The heart hypertrophies in response to developmental signals as well as increased workload. Although adult-onset hypertrophy can ultimately lead to disease, cardiac hypertrophy is not necessarily maladaptive and can even be beneficial. Progress has been made in our understanding of the structural and molecular characteristics of physiological cardiac hypertrophy, as well as of the endocrine effectors and associated signalling pathways that regulate it. Physiological hypertrophy is initiated by finite signals, which include growth hormones (such as thyroid hormone, insulin, insulin-like growth factor 1 and vascular endothelial growth factor) and mechanical forces that converge on a limited number of intracellular signalling pathways (such as PI3K, AKT, AMP-activated protein kinase and mTOR) to affect gene transcription, protein translation and metabolism. Harnessing adaptive signalling mediators to reinvigorate the diseased heart could have important medical ramifications.

Figure 1. Physiological hypertrophy signalling pathways

Physiological hypertrophy is an adaptive form of cardiac hypertrophy. The figure depicts central signalling pathways of physiological hypertrophy discussed in the text. Physiological hypertrophy is initiated by intermittent signals of triiodothyronine (T3), vascular endothelial growth factor B (VEGFB), insulin and insulin-like growth factor 1 (IGF1), as illustrated by the oscillating curve. The growth hormones activate membrane-localized tyrosine kinase receptors (VEGF receptor 1 (VEGFR1), IGF1 receptor (IGF1R) or insulin receptor (IR)) and nuclear receptors (thyroid hormone receptor (TR)), which trigger intracellular signalling pathways specific to physiological hypertrophy. These signalling pathways regulate the transcription of adaptive genes, protein synthesis, metabolism and energy production. The growth signals centre on common signalling branches controlled by ERK1/2, PI3K, AKT and mTOR complex 1 (mTORC1), whereas AMP-activated protein kinase (AMPK) governs metabolic adaptive reprogramming. 4EBP1, eukaryotic translation initiation factor 4E-binding protein 1; C/EBPβ, CCAAT/enhancer binding protein-β; CaMKKβ, calcium/calmodulin-dependent protein kinase kinase-β; CITED4, CBP/p300 interacting transactivator 4; eIF2Bε, eukaryotic translation initiation factor 2Bε; FOXO, forkhead box O; GSK3β, glycogen synthase kinase 3β; IRS1/2, insulin receptor substrate 1 or 2; LKB1, liver kinase B1; PDK1, phosphoinositide-dependent protein kinase 1; PGC1α, peroxisome proliferator-activated receptor-γ co-activator 1α; RHEB, RAS homologue enriched in brain; RXR, retinoic acid receptor; S6K, S6 kinase; SRF, serum response factor; TAK1, transforming growth factor β-activated kinase 1; TSC1/2, tuberous sclerosis complex 1 or 2.

Figure 2. Stretch-mechanosensing in the initiation of physiological hypertrophy

Mechanotransduction converts mechanical forces into biochemical signals. Activation of transient receptor potential canonical (TRPC) channels by stretch leads to calcium influx and the activation of hypertrophic signalling pathways. Changes in the extracellular matrix (ECM) are sensed by integrins that signal through RHO GTPases, integrin-linked kinase (ILK), focal adhesion kinase (FAK), protein kinase C (PKC) and the pro-hypertrophic PI3K and ERK1/2. Stretch is also sensed within the sarcomeres at the Z line by proteins such as muscle LIM protein (MLP), actinin-associated LIM protein (ALP), nebulette (NEB), cypher, telethonin (Tele), obscurin (Obs) and the giant protein titin that senses both strain and stretch.