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1.
J Am Heart Assoc ; 6(5)2017 May 04.
Article in English | MEDLINE | ID: mdl-28473402

ABSTRACT

BACKGROUND: Heart failure is a common secondary complication following a myocardial infarction (MI), characterized by impaired cardiac contraction and t-tubule (t-t) loss. However, post-MI nano-scale morphological changes to the remaining t-ts are poorly understood. METHOD AND RESULTS: We utilized a porcine model of MI, using a nonlethal microembolization method to generate controlled microinfarcts. Using serial block face scanning electron microscopy, we report that post-MI, after mild left-ventricular dysfunction has developed, t-ts are not only lost in the peri-infarct region, but also the remnant t-ts form enlarged, highly branched disordered structures, containing a dense intricate inner membrane. Biochemical and proteomics analyses showed that the calcium release channel, ryanodine receptor 2 (RyR2), abundance is unchanged, but junctophilin-2 (JP2), important for maintaining t-t trajectory, is depressed (-0.5×) in keeping with the t-ts being disorganized. However, immunolabeling shows that populations of RyR2 and JP2 remain associated with the remodeled t-ts. The bridging integrator 1 protein (BIN-1), a regulator of tubulogensis, is upregulated (+5.4×), consistent with an overdeveloped internal membrane system, a feature not present in control t-ts. Importantly, we have determined that t-ts, in the remote region, are narrowed and also contain dense membrane folds (BIN-1 is up-regulated +3.4×), whereas the t-ts have a radial organization comparable to control JP2 is upregulated +1.7×. CONCLUSIONS: This study reveals previously unidentified remodeling of the t-t nano-architecture in the post-MI heart that extends to the remote region. Our findings highlight that targeting JP2 may be beneficial for preserving the orientation of the t-ts, attenuating the development of hypocontractility post-MI.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Membrane Proteins/metabolism , Myocardial Infarction/metabolism , Myocardium/metabolism , Sarcolemma/metabolism , Ventricular Function, Left , Ventricular Remodeling , Animals , Disease Models, Animal , Heart Failure/etiology , Heart Failure/metabolism , Heart Failure/pathology , Heart Failure/physiopathology , Myocardial Contraction , Myocardial Infarction/complications , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardium/ultrastructure , Ryanodine Receptor Calcium Release Channel/metabolism , Sarcolemma/ultrastructure , Sus scrofa , Ventricular Dysfunction, Left/etiology , Ventricular Dysfunction, Left/metabolism , Ventricular Dysfunction, Left/pathology , Ventricular Dysfunction, Left/physiopathology
2.
Nat Commun ; 5: 3775, 2014 May 13.
Article in English | MEDLINE | ID: mdl-24825544

ABSTRACT

Endurance athletes exhibit sinus bradycardia, that is a slow resting heart rate, associated with a higher incidence of sinus node (pacemaker) disease and electronic pacemaker implantation. Here we show that training-induced bradycardia is not a consequence of changes in the activity of the autonomic nervous system but is caused by intrinsic electrophysiological changes in the sinus node. We demonstrate that training-induced bradycardia persists after blockade of the autonomous nervous system in vivo in mice and in vitro in the denervated sinus node. We also show that a widespread remodelling of pacemaker ion channels, notably a downregulation of HCN4 and the corresponding ionic current, If. Block of If abolishes the difference in heart rate between trained and sedentary animals in vivo and in vitro. We further observe training-induced downregulation of Tbx3 and upregulation of NRSF and miR-1 (transcriptional regulators) that explains the downregulation of HCN4. Our findings provide a molecular explanation for the potentially pathological heart rate adaptation to exercise training.


Subject(s)
Bradycardia/genetics , Heart Rate/genetics , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics , Physical Conditioning, Animal , RNA, Messenger/metabolism , Sinoatrial Node/metabolism , Adaptation, Physiological/genetics , Animals , Bradycardia/metabolism , Down-Regulation , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism , In Vitro Techniques , Mice , MicroRNAs/genetics , MicroRNAs/metabolism , Rats , Repressor Proteins/genetics , Repressor Proteins/metabolism , T-Box Domain Proteins/genetics , T-Box Domain Proteins/metabolism , Up-Regulation
3.
Exp Physiol ; 96(9): 875-88, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21622965

ABSTRACT

This study tested the hypothesis that experimental prediabetes can elicit structural remodelling in the left ventricle (LV). Left ventricles isolated from 8-week-old male Goto-Kakizaki (GK) rats and age-matched male Wistar control rats were used to assess remodelling changes and underlying transforming growth factor ß1 (TGFß1) activity, prohypertrophic Akt-p70S6K1 signalling and gene expression profile of the extracellular matrix (ECM) using histological, immunohistochemical, immunoblotting and quantitative gene expression analyses. Prediabetes in GK rats was confirmed by impaired glucose tolerance and modestly elevated fasting blood glucose. Left ventricle remodelling in the GK rat presented with marked hypertrophy of cardiomyocytes and increased ECM deposition that together translated into increased heart size in the absence of ultrastructural changes or fibre disarray. Molecular derangements underlying this phenotype included recapitulation of the fetal gene phenotype markers B-type natriuretic peptide and α-skeletal muscle actin, activation of the Akt-p70S6K1 pathway and altered gene expression profile of key components (collagen 1α and fibronectin) and modulators of the ECM (matrix metalloproteinases 2 and 9 and connective tissue growth factor). These changes were correlated with parallel findings of increased TGFß1 transcription and activation in the LV and elevated active TGFß1 in plasma of GK rats compared with control animals (Student's t test, P < 0.05 versus age-matched Wistar control animals for all parameters). This is the first report to describe LV structural remodelling in experimental prediabetes. The results suggest that ventricular decompensation pathognomonic of advanced diabetic cardiomyopathy may have possible origins in profibrotic and prohypertrophic mechanisms triggered before the onset of type 2 diabetes mellitus.


Subject(s)
Prediabetic State/physiopathology , Transforming Growth Factor beta1/metabolism , Ventricular Remodeling , Animals , Cardiomegaly/metabolism , Diabetes Mellitus, Type 2/physiopathology , Extracellular Matrix Proteins/metabolism , Heart Ventricles/metabolism , Male , Natriuretic Peptide, Brain , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Inbred Strains , Rats, Wistar , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Signal Transduction/physiology
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