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Cardiac remodelling

Schematic diagram of cardiac fibrogenesis cascade and its contribution to atrial fibrillation (AF)
Yue L et al. Cardiovasc Res 2011; 89:744-753 - Click here to view the abstract 

In response to a variety of stimuli, cardiac fibroblasts proliferate, differentiate, synthesize extracellular matrix (ECM) proteins, and produce cytokines like transforming growth factor-beta (TGFβ) and interleukin-6 (IL6) that in turn stimulate fibroblasts, thereby providing positive feedback that amplifies and perpetuates the fibrogenesis cascade. ECM accumulation causes fibrosis that favours the occurrence and maintenance of AF. There are two types of fibrosis, responsive and reparative, that can be caused by many common stimuli, with reparative fibrosis being particularly involved in repairing tissues after cardiomyocyte death. Fibrosis promotes AF by acting as a conductive barrier that impedes impulse propagation and/or via proarrhythmic cellular interactions between cardiomyocytes and fibroblasts. Intracellular Ca2+ signals mediated by transient receptor potential (TRP) channels, in particular TRP melastatin-related 7 (TRPM7) channels, are critical for fibroblast proliferation, differentiation, and ECM production in fibroblasts from AF patients. Ca2+ release may affect fibroblast function via the modulation of gene expression through Ca2+-dependent transcription factors (TFs). Fibroblast Ca2+ signalling may be an effective target for the prevention of fibrogenesis and could be a novel approach to AF therapy.

Mechanisms of atrial structural changes caused by stretch occurring before and during early atrial fibrillation
De Jong A M et al. Cardiovasc Res 2011; 89:754-765 - Click here to view the abstract

A schematic representation of the calcium homeostasis and events that may take place due to calcium overload induced by AF. Depolarization of the cardiomyocyte leads to inflow of calcium into the cell via (i) L-type Ca2+-channels, (ii) reverse mode Na+/Ca2+-exchanger, and (iii) T-type Ca2+-channels. This induces calcium-induced-calcium release from the sarcoplasmic reticulum via ryanodine receptors (RyR) into the cytoplasm. Calcium, subsequently, binds to contractile elements and initiates contraction. In the diastole, calcium leaves the cytoplasm via sarcoplasmic reticulum Ca2+-ATPase (SERCA), which is regulated by phospholamban (Pln), and via the Na+/Ca2+-exchanger and plasma membrane Ca2+-ATPase.

Ions can also leave and enter the cell via stretch-activated channels (SAC). During AF calcium overload can contribute to an altered signal transduction. Activation of Ca2+-dependent proteins such as calpain, calcineurin, and calcium/calmodulin-dependent protein kinase II (CaMKII) may be increased. Activation of calpain may result in degradation of muscle proteins (myolysis). Increased calcineurin activation activates NFAT (nuclear factor of activated T-cells) by dephosphorylation and CaMKII activates myocyte enhancer factor 2 (MEF2) signalling. Both lead to altered gene expression such as increased ANP and BNP expression and hypertrophy. Calsarcin, a stretch-sensitive protein localized to the Z-disk, is an inhibitor of calcineurin. The plasma membrane calcium-ATPase fine tunes diastolic calcium levels and inhibits calcineurin via direct binding.

‘Turning the right screw’: targeting the interleukin-6 receptor to reduce unfavourable tissue remodelling after myocardial infarction

Möllmann H et al. Cardiovasc Res (2010) 87(3): 395-396 first published online June 16, 2010 doi:10.1093/cvr/cvq186 - Click here to view the abstract 

Partial overview of targets and mechanisms involved in LV remodelling after myocardial infarction (MI). Early inhibition of IL-6 signalling using an anti-IL-6 receptor antibody (M16-1) leads to decreased mortality after MI, mainly through reduction of inflammation and extracellular matrix remodelling of the healthy surrounding myocardial tissue. Infarct size and apoptosis were not altered by interference with IL-6 receptor signalling.
Partial overview of targets and mechanisms involved in LV remodelling after myocardial infarction (MI). Early inhibition of IL-6 signalling using an anti-IL-6 receptor antibody (M16-1) leads to decreased mortality after MI, mainly through reduction of inflammation and extracellular matrix remodelling of the healthy surrounding myocardial tissue. Infarct size and apoptosis were not altered by interference with IL-6 receptor signalling.

Paradigm of intracellular and extracellular MMP-2 in cardiac myocytes
Kandasamy AD et al. Cardiovasc Res (2010) 85(3): 413-423 first published online August 4, 2009 doi:10.1093/cvr/cvp268 - Click here to view the abstract 

MMP-2 is present in discrete intracellular compartments within the cardiac myocyte (sarcomere, nuclei, caveolae, and mitochondria) as a 72 kD zymogen. It can be activated in two ways that likely dictate its diverse biological roles. Its secretion and proteolytic removal of its autoinhibitory propeptide domain by MT1-MMP together with TIMP-2 results in a 64 kD form that targets extracellular matrix proteins. Oxidative stress, particularly as ONOO- in the presence of glutathione, causes the S-glutathiolation of a critical cysteine residue in the propeptide and conformational change and activation of the 72 kD form, allowing access of intracellular substrates (troponin I, α-actinin, myosin light chain-1, and titin are thus far known) to its catalytic zinc centre. MMP-2 is also a phosphoprotein (both 72 and 64 kD forms) and phosphorylation markedly reduces its activity (FASEB J 2007;21:2486). The kinases and phosphatases that regulate its activity in vivo are unknown; however, PKC can phosphorylate MMP-2 in vitro. Thus, MMP-2 can ‘remodel’ both intracellular and extracellular protein substrates. The cleavage of intracellular substrates by MMP-2 is an early response to enhanced oxidative stress that results in acute contractile dysfunction.

Abbreviations: matrix metalloproteinase-2 (MMP-2); tissue inhibitor of metalloproteinase-2 (TIMP-2); membrane-type-1 matrix metalloproteinase (MT1-MMP); glutathione (GSH); peroxynitite (ONOO-); protein kinase A (PKA); protein kinase C (PKC)

A schematic illustration of protein quality control (PQC) in the cell
Su H & Wang X Cardiovasc Res (2010) 85(2): 253-262 first published online August 20, 2009 doi:10.1093/cvr/cvp287 - Click here to view the abstract

PQC is carried out by chaperones, the ubiquitin proteasome system (UPS), and the autophagy-lysosome pathway. Chaperones facilitate the folding of nascent polypeptides and the unfolding/refolding of misfolded proteins, prevent the misfolded proteins from aggregating, and escort terminally misfolded proteins for degradation by the UPS. The UPS degrades misfolded proteins and unneeded native proteins in the cell through two general steps: first, covalent attachment of ubiquitin to a target protein by a cascade of chemical reactions catalysed by the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligase (E3); second, the degradation of the target protein by the proteasome. The autophagy-lysosomal pathway helps remove protein aggregates formed by the misfolded proteins that have escaped from the surveillance of chaperones and the UPS. Protein aggregates or defective organelles are first segregated by an isolated double membrane (phagophore) to form autophagosomes, which later fuse with lysosomes to form autophagolysosomes, where the segregated content is degraded by lysosomal hydrolases. p62/SQSTM1 and NBR1 (neighbour of BRCA1 gene 1) may mediate the activation of autophagy by aggregated ubiquitinated proteins. The legend for symbols used is shown in the box at the lower left.
 
PQC is carried out by chaperones, the ubiquitin proteasome system (UPS), and the autophagy-lysosome pathway. Chaperones facilitate the folding of nascent polypeptides and the unfolding/refolding of misfolded proteins, prevent the misfolded proteins from aggregating, and escort terminally misfolded proteins for degradation by the UPS. The UPS degrades misfolded proteins and unneeded native proteins in the cell through two general steps: first, covalent attachment of ubiquitin to a target protein by a cascade of chemical reactions catalysed by the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligase (E3); second, the degradation of the target protein by the proteasome. The autophagy-lysosomal pathway helps remove protein aggregates formed by the misfolded proteins that have escaped from the surveillance of chaperones and the UPS. Protein aggregates or defective organelles are first segregated by an isolated double membrane (phagophore) to form autophagosomes, which later fuse with lysosomes to form autophagolysosomes, where the segregated content is degraded by lysosomal hydrolases. p62/SQSTM1 and NBR1 (neighbour of BRCA1 gene 1) may mediate the activation of autophagy by aggregated ubiquitinated proteins. The legend for symbols used is shown in the box at the lower left.

Vicious relationship between wall stress and ventricular remodelling to aggravate postinfarction heart failure
Takemura G et al. Cardiovasc Res (2009) 83(2): 269-276 first published online January 28, 2009 doi:10.1093/cvr/cvp032 - Click here to view the abstract


(A) Transverse ventricular sections taken from mouse hearts on Day 3, 7, or 28 postinfarction and stained with Masson's trichrome. Left ventricular remodelling progresses with time following myocardial infarction (MI). (B) Photomicrographs of infarct tissue collected from mouse hearts on Day 3, 7, or 28 post-MI, showing, respectively, acute inflammation, granulation, and scar. (C) With the passage of time after the onset of MI, the infarct length and left ventricular cavity become larger, whereas the infarct wall thickness decreases. Wall stress is proportional to the cavity diameter and intracavitary pressure and inversely proportional to the wall thickness (Laplace's law). Thus, wall stress and ventricular remodelling (dilatation and wall thinning) have a vicious relationship, aggravating one another and exacerbating post-infarction heart failure.

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.

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. 

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.

Disruption of fuel servicing in the myocardium: from ‘eutaxy and efficiency’ to ‘ataxy and inefficiency’

Saikawa T Cardiovasc Res (2011) 92(1): 3-4 doi:10.1093/cvr/cvr231 - Click here to view the abstract 

Deletion of PGC-1β leads to disruption of mitohormesis and arrhythmias in cardiomyocytes.

A tentative scheme is shown that depicts how PPAR-γ or PGC-1s stimulation and suppression modulate electrical activity in cardiomyocytes. For biological activity, PPAR-γ needs coactivation by PGC-1α/β. These coactivators are inducible and play a vital role in cellular ATP production and mitochondrial function.
Exogenous stress stimulates the expression of chemokines and adhesion molecules in the heart. These molecules promote atrial fibrosis on the one hand, and macrophage recruitment and inflammation on the other, which result in heart failure and arrhythmias substrate formation.
The suppression or deletion of PGC-1β seems to result in variable electrical instabilities and arrhythmias, especially during adrenergic stress. An imbalance of mitochondrial ATP production is noted as well, which is arrhythmogenic by itself. The stimulation of PPARγ; blocks stress-induced expression of chemokines and adhesion molecules. The recruitment of macrophages from storage sites such as splenic red pulp (red bar) is also suppressed, resulting in an improvement of atrial fibrosis and mitochondrial function. Details of signaling cascades mediated by the PPARγ-PGC-1 axis that leads to electrical instability are waiting to be elucidated.