Hypertrophy

The nonsense-mediated mRNA decay – a mRNA surveillance pathway

Carrier L et al. Cardiovasc Res (2010) 85(2): 330-338 first published online July 17, 2009 doi:10.1093/cvr/cvp247 - Click here to view the abstract

MYBPC3 is one of the most frequently mutated genes in hypertrophic cardiomyopathy (HCM). Most mutations result in a frameshift and a premature termination codon (PTC) and should produce truncated proteins, which were never detected in myocardial tissue of patients. Recent data showed that the nonsense-mediated mRNA decay (NMD) is involved in the degradation of nonsense mRNA in a mouse model of HCM (Vignier, Schlossarek et al., Circ Res 2009). NMD is an evolutionarily conserved pathway existing in all eukaryotes that detects and eliminates PTC-containing transcripts. NMD apparently evolved to protect the organism from the deleterious dominant-negative or gain-of-function effects of resulting truncated proteins.

(A) NMD occurs when a PTC is located more than 50–55 nucleotides (nt) upstream of the last exon–exon junction within the mRNA (green region), whereas mRNAs with PTCs downstream of this boundary (red region) escape NMD. (B) During pre-mRNA splicing, exon junction complexes (EJC) are deposited upstream of every exon–exon junction. In normal transcripts, EJCs are displaced by the ribosome during the pioneer round of translation, and translation stops when the ribosome reaches the normal stop codon. In contrast, in PTC-bearing mRNAs, the ribosome is blocked at the PTC and the EJC downstream of the PTC remains associated with the mRNA. This results in attachment of the SURF complex to the ribosome. Subsequent phosphorylation of UPF1 by SMG-1 drives dissociation of eRF1 and eRF3 and binding of SMG7. Ultimately, the mRNA is degraded by different pathways including decapping or deadenylation.

VEGF receptor switching in heart development and disease

Cardiovasc Res (2009) 84(1): 4-6 first published online August 4, 2009 doi:10.1093/cvr/cvp270 - Click here to view the abstract

A schematic representation of the cardiomyocyte VEGF signalling pathway. Flt-1 and KDR are the two major VEGF receptors. In cardiomyocytes, VEGF drives cardiac hypertrophy or its regression, depending on the prevalent binding to KDR or Flt-1, respectively. Copper (Cu) supplementation determines a switch in the VEGF signalling pathway, increasing the ratio of Flt-1 to KDR. By this mechanism, copper induces regression of cardiomyocyte hypertrophy.

Abbreviations: VEGF, vascular endothelial growth factor; Flt-1, FMS-like tyrosine kinase-1; KDR, kinase insert domain receptor; PKG-1, cGMP-dependent protein kinase-1; Cu, copper; DAG, diacylglycerol; IP3, inositol trisphosphate; Sos, Son of Sevenless; Shc, Src-homology collagen protein; Grb-2, growth factor receptor-bound protein 2; MEK1/2, mitogen activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) kinase 1/2; PKC, protein kinase C; PLC-γ, phospholipase C-γ; PD98059 (PD) and UO126 are selective ERK1/2 inhibitors.

Enigma in cardiac hypertrophy

Lompré AM Cardiovasc Res (2010) 86(3): 349-350 first published online March 23, 2010 doi:10.1093/cvr/cvq094 - Click here to view the abstract

Schematic representation of a hypothetical pathway by which the splice variants of ENH could promote or prevent hypertrophy.

The Enigma proteins (ENH) are cytoplasmic proteins that bind to the cytoskeleton and serve as a platform for binding many proteins such as protein kinases. Four ENH isoforms have been described. ENH1, which contains the LIM motif, is expressed in the embryonic and neonatal heart. In the adult heart it is replaced by ENH3, which does not contain this binding motif (Yamazaki et al. Cardiovasc Res 2010,86:374-382). Based upon previously published data showing that the LIM domain anchors PKC and PKD and taking into account the well-described molecular pathways implicated in the hypertrophic effect of these kinases, it is tempting to propose that the LIM domains of ENH1 act as a new signalling platform that mediates the PKC and PKD hypertrophic pathways.

Abbreviations: ENH1-PDZ, enigma homologue 1 PDZ (PSD-95, DLG, ZO-1) domain; ENH1-Lim, enigma homologue 1 Lim (LIN-11, Isl-1, MEC-3) domains; LTCC, L-type voltage-gated Ca²⁺ channel; PKD1, protein kinase D1; PKC, protein kinase C; Id, inhibitor of differentiation/DNA binding; CaMK, Ca²⁺calmodulin kinase; 14-3-3, chaperone protein 14-3-3; HDAC4,5,9, histone deacetylase type 4, 5, and 9; MEF2, myocyte enhancing factor 2; P, phosphorylation.