A pictorial representation of adjacent cardiomyocytes illustrating the genes implicated in Mendelian forms of atrial fibrillation and the presumed mechanism of action of the mutations.
Mahida S et al. Cardiovasc Res 2011; 89:692-700 - Click here to view the abstract
The majority of mutations have been identified in ion channel subunit genes and lead to either gain-of-function or loss-of-function effects. Gain-of-function potassium channel mutations have been identified in KCNQ1, KCNE2, KCNE5 and KCNJ2. KCNQ1, KCNE2 and KCNE5 encode subunits of the cardiac IKS channel while KCNJ2 encodes a subunit of the IK1 channel. A loss-of-function potassium channel gene mutation has been reported in KCNA5, which encodes a subunit of the IKur channel. Both gain-of-function and loss-of-function mutations have been identified in SCN5A, which encodes the α subunit of the cardiac sodium channel. Loss-of-function mutations have also been reported in SCN1B and SCN2B, genes encoding β subunits of the cardiac sodium channel.
Non-ion channel gene mutations have also been implicated in familial AF. These include mutations in NUP155, GJA5 and NPPA. NUP155 encodes a nucleoporin, which is a molecular component of nuclear pore complexes. GJA5 encodes connexin-40, an atrial gap junction protein which plays a role in cell-to-cell electrical coupling. The reported NPPA mutation is associated with markedly elevated levels of mutant atrial natriuretic.
The first step of the canonical pathway of miRNA biogenesis involves generation of primary miRNAs (pri-miRNAs) with a stem–loop structure through transcription of miRNA genes. The pri-miRNA is subsequently processed to become precursor miRNAs (pre-miRNAs) by the nuclear RNase endonuclease III Drosha in the nucleus. The pre-miRNAs are then exported to the cytoplasm from the nucleus through the nuclear pores exportin-5. In the cytoplasm, pre-miRNAs are further processed by another RNase III, Dicer, to become ~22 nucleotide duplexes of mature miRNAs. Incorporation of mature miRNA into the protein complex called RNA-induced silencing complex (RISC) to form miRISC is the first step for its action in gene regulation. One of the double strands, the passenger strand, is eliminated, while the remaining strand, the guide strand, serves to guide miRISC to find its complementary motif(s), mainly in the 3′-untranslated region of the target mRNA through a Watson–Crick base-pairing mechanism with its 5′ end 2-8 nucleotides exactly complementary to the recognition motif. This 5′-end 2-8 nucleotide region is termed the ‘seed site’ because it is critical for miRNA actions.
Abbreviations: Pol II, polymerase II; Pol III, polymerase III; pri-miRNA, primary miRNA; pre-miRNA, precursor miRNA; RISC, RNA-induced silencing complex; miRISC, miRNA incorporated RISC; and ORF, open reading frame.
High glucose, nitric oxide, and adenosine: a vicious circle in chronic hyperglycaemia?
Cardiovasc Res (2010) 86(1): 9-11 first published online February 17, 2010 doi:10.1093/cvr/cvq055 - Click here to view the abstract
High glucose, NO, and adenosine: a vicious circle in chronic hyperglycaemia.
HUVEC isolated from gestational diabetic pregnancies show a reduced adenosine transport activity via hENT1. This effect of gestational diabetes leads to extracellular accumulation and a higher bioavailability of this nucleoside to activate the A2a adenosine receptor subtype. The intracellular signalling cascade triggered by A2a purinoreceptor activation by adenosine results in an increased l-arginine transport activity via hCATs and increased NO synthesis by eNOS. The intracellular second messengers involved in the effect of adenosine include activation of protein kinase C (PKC) and 42/44 kDa mitogen-activated protein kinases (P42/44mapk), which then activate (+) l-arginine transport. The up-regulation in the endothelial l-arginine/NO pathway by adenosine is associated with an increase in NO. NO activates hCHOP and C/EBPα transcription factor complex formation, which migrates to the nucleus of the endothelial cells and binds, as a complex, to a consensus sequence located on the promoter region of the SLC29A1 gene (for hENT1).
This phenomenon results in reduced transcriptional activity of the SLC29A1 promoter, leading to reduced levels of the hENT1 mRNA and protein. As a consequence, a decreased hENT1 transport-like activity could result in reducing the removal of the endogenous nucleoside adenosine from the extracellular medium in HUVEC. The reduced adenosine transport via hENT1 detected in HUVEC from gestational diabetes could also result from the inhibition (−) by PKC or P42/44mapk. Notably, hyperglycaemia (glucose) may be proposed as a regulator of the illustrated vicious circle since it might increase (+) both eNOS and NO levels. hCHOP, a key transcriptional regulator of the SLC29A1 gene, has been demonstrated to be increased (+) by high glucose and diabetes.
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.
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.
KATP channel-dependent metaboproteome decoded: systems approaches to heart failure prediction, diagnosis, and therapy
Arrell DK et al. Cardiovasc Res (2011) 90(2): 258-266 doi:10.1093/cvr/cvr046 - Click here to view the abstract
Forecasting cardiac outcome from a presymptomatic proteomic signature. (A) At baseline, no differences were observed in cardiac structure or function between age- and sex-matched wild-type and Kir6.2 KATP channel knockout cohorts. Left ventricular tissue was extracted for proteomic analysis by comparative 2D gel electrophoresis resolution. (B) Statistical analysis of quantified 2D gel images indicated significant differences in 9% of detected protein species, subsequently isolated and identified by tandem mass spectrometry and categorized by primary protein function, revealing a metabolism-centric theme of protein change. (C) Altered proteins served as focus proteins for network analysis, with Ingenuity Pathways Knowledge Base expanding the KATP channel-dependent changes into a broader network neighbourhood, which reinforced the metabolic focus of measured changes both by ontological function (shown) and by ontological assessment of overrepresented biological processes (not shown).34
(D) Bioinformatic interrogation of proteome changes and their expanded network, for the presence of potential adverse effects, indicated an overrepresentation of markers associated with susceptibility to cardiac disease. Subsequent experimental imposition of graded stress validated disease susceptibility, with the Kir6.2 deficient cohort exhibiting progressively deleterious structural and functional cardiac defects, ultimately decreasing survival. *P< 0.05 vs. WT counterparts; **P< 0.01 vs. WT counterparts.
NO points to epigenetics in vascular development
Illi B et al. Cardiovasc Res (2011) 90(3): 447-456 doi:10.1093/cvr/cvr056 - Click here to view the abstract
A model for NO-dependent epigenetic effect during ESC vascular differentiation. NO may be produced both by ligand-activated receptors and environmental cues (e.g. shear stress), which activate the PI3K/Akt pathway leading to eNOS phosphorylation. Cytosolic NO, in turn, induces class II HDACs nuclear translocation via PP2A activation and post-translational modification (mainly tyrosine nitration and S-nitrosylation) of transcription factors. NO may exert its function in the nucleus after diffusion from the cytosol. Further, it may be directly produced by the nuclear eNOS (ref). In the nuclear compartment, NO post-translationally modify HDAC2 and transcription factors. Altogether, these processes lead both to the repression of stem and non-mesodermal genes and to the activation of vascular genes. Tyr-nitration, tyrosine nitration; BH4, tetrahydrobiopterin.
Parathyroid hormone is a DPP-IV inhibitor and increases SDF-1-driven homing of CXCR4+ stem cells into the ischaemic heart
Huber BC et al. Cardiovasc Res (2011) 90(3): 529-537 doi:10.1093/cvr/cvr014 - Click here to view the abstract
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.
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