Signaling to cardiac hypertrophy: insights from human and mouse RASopathies

Abstract

Cardiac hypertrophy is the heart's response to a variety of extrinsic and intrinsic stimuli, some of which might finally lead up to a maladaptive state. An integral part of the pathogenesis of the hypertrophic cardiomyopathy disease (HCM) is the activation of the rat sarcoma (RAS)/RAF/MEK (mitogen-activated protein kinase kinase)/MAPK (mitogen-activated protein kinase) cascade. Therefore, the molecular signaling involving RAS has been the subject of intense research efforts, particularly after the identification of the RASopathies. These constitute a class of developmental disorders caused by germline mutations affecting proteins contributing to the RAS pathway. Among other phenotypic features, a subset of these syndromes is characterized by HCM, prompting researchers and clinicians to delve into the chief signaling constituents of cardiac hypertrophy. In this review, we summarize current advances in the knowledge of the molecular signaling events involved in the pathogenesis of cardiac hypertrophy through work completed on patients and on genetically manipulated animals with HCM and RASopathies. Important insights are drawn from the recognition of parallels between cardiac hypertrophy and cancer. Future research promises to further elucidate the complex molecular interactions responsible for cardiac hypertrophy, possibly pointing the way for the identification of new specific targets for the treatment of HCM.

Figure 1

Schematic representation of RAS pathway and its correlation with RASopathies. A growth factor activates its RTK causing phosphorylation of tyrosines, which are bound by adapter proteins, SHC/GRB2 and GAB. These interact with the activators of RAS, SOS1 and SHP2, and induce the dissociation of GDP and binding of GTP. RAS-GTP activates a cascade of downstream kinases: the MAPK pathway. On the other hand, the inhibition of RAS signaling is mediated by GAPs: RASA1 and neurofibromin 1. The RASopathies are developmental pathologies due to mutations on genes encoding proteins of the RAS pathway. HCM is uncommon in NS and CFC patients. However, nearly all NS patients with mutated RAF1 develop HCM. PTPN11 (encoding SHP2) loss-of-function mutations were observed in the majority of LS patients who developed HCM. Mutations in RAF1 have also been identified in a small percentage of LS with HCM. CS patients harboring HRAS mutations consistently show cardiac hypertrophy. Light gray shading indicates the mutation-specific syndromes accompanied by HCM; dark gray shading indicates those syndromes in which cardiac hypertrophy is less common.

Figure 2

RAS Network: cross-links in hypertrophy. The cardiac hypertrophic response implicates signal transduction pathways initiated by ligand-stimulated membrane-bound receptors (RTKs, GPCRs) and biomechanical stress sensors (integrins). Various signaling effectors interact with the RAS/MEK/MAPK pathway. GPCR receptors activate RAS proteins through EPAC, induce release of internal Ca2+ stores and elicit pathological hypertrophy through calcineurin/NFAT. GPCRs also act through ERK activation. GSK3 kinase negatively regulates NFAT and, in turn, is inactivated by the PI3K-AKT pathway stimulated by RAS. Stimuli acting on integrins prompt cardiac hypertrophy through FAK activation and considerable cross-talk with RTK-mediated signaling. In addition, PAK regulates RAF1 activity. All these pathways converge on the modulation of transcriptional factors (MEF2, JUN and GATA4), which induce the expression of genes of the hypertrophic program.