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.
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.
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.
Prior research has identified major changes in cardiac metabolism during the development of pathological hypertrophy. The hallmark of these changes is a reduction in the contribution of fatty acids to oxidative metabolism. As a result, the hypertrophied heart shifts to increased reliance on glucose metabolism. Specifically, increased glucose uptake and accelerated glycolysis occur in cardiac hypertrophy with increased activity of LDH and lactate efflux. Despite this, oxidation of pyruvate is not increased, which demonstrates an “uncoupling” of glycolysis and glucose oxidation. However, the potential of excess pyruvate to enter the TCA cycle through anaplerosis, specifically via malic enzyme, has been recently shown. Although the glycolytic pathway is upregulated, studies have not shown a consistent upregulation of accessory pathways of glucose metabolism in pathological cardiac hypertrophy. Glycogen content and its contribution to metabolism remain unchanged. Although increased activity of G6PD has been found, no changes in flux or enzymes involved in the pentose phosphate pathway have been identified. Additionally, the role of the aldose reductase pathway in cardiac hypertrophy has not been elucidated. Considerable work has identified increased expression of GFAT as well as increased flux through the hexosamine biosynthetic pathway in pressure-overload hypertrophy and heart failure.
Legend: Key changes in the metabolic pathway have been colour coded. Green: increased; Red: decreased; Blue: no change; Black: unknown.
Abbreviations: F-6-P, fructose-6-phosphate; G-6-P, glucose-6-phosphate; G6PD, glucose-6-phosphate dehydrogenase; GFAT, glutamine fructose-6-phosphate amidotransferase; GLUT, glucose transporter; LDH, lactate dehydrogenase; ME, malic enzyme; NADH, reduced nicotinamide adenine dinucleotide; OMC, oxoglutarate-malate carrier; TCA, tricarboxylic acid.
Parathyroid hormone is a DPP-IV inhibitor and increases SDF-1-driven homing of CXCR4+ stem cells into the ischaemic heart
Mechanism of PTH-mediated cardioprotection. PTH administration after MI induces mobilization of stem cells from the BM to the peripheral blood. These stem cells circulate to the damaged heart, where they are incorporated by interaction of intact myocardial SDF-1 and the homing receptor CXCR4. PTH inhibits DPP-IV activity and thereby prevents the degradation of intact SDF-1. Thus, an increased amount of SDF-1 improves homing of mobilized CXCR4+ cells. Altogether, PTH reduced cardiac remodelling after MI and enhanced cardiac function by attenuating the development of ischaemic cardiomyopathy.