Tail-anchored membrane protein SLMAP is a novel regulator of cardiac function at the sarcoplasmic reticulum

2012 ◽  
Vol 302 (5) ◽  
pp. H1138-H1145 ◽  
Author(s):  
Moni Nader ◽  
Bart Westendorp ◽  
Omar Hawari ◽  
Maysoon Salih ◽  
Alexandre F. R. Stewart ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Qt Interval ◽  
Cardiac Electrophysiology ◽  
Transmembrane Domain ◽  
Left Ventricular ◽  
Confocal Imaging ◽  
Expression Level ◽  
Subcellular Targeting ◽  
Functional Disturbances ◽  
And Function

Sarcolemmal membrane-associated proteins (SLMAPs) are components of cardiac membranes involved in excitation-contraction (E-C) coupling. Here, we assessed the role of SLMAP in cardiac structure and function. We generated transgenic (Tg) mice with cardiac-restricted overexpression of SLMAP1 bearing the transmembrane domain 2 (TM2) to potentially interfere with endogenous SLMAP through homodimerization and subcellular targeting. Histological examination revealed vacuolated myocardium; the severity of which correlated with the expression level of SLMAP1-TM2. High resolution microscopy showed dilation of the sarcoplasmic reticulum/endoplasmic reticulum (SR/ER) and confocal imaging combined with biochemical analysis indicated targeting of SLMAP1-TM2 to the SR/ER membranes and inappropriate homodimerization. Older (28 wk of age) Tg mice exhibited reduced contractility with impaired relaxation as assessed by left ventricle pressure monitoring. The ventricular dysfunction was associated with electrophysiological abnormalities (elongated QT interval). Younger (5 wk of age) Tg mice also exhibited an elongated QT interval with minimal functional disturbances associated with the activation of the fetal gene program. They were less responsive to isoproterenol challenge (ΔdP/d tmax) and developed electrical and left ventricular pressure alternans. The altered electrophysiological and functional disturbances in Tg mice were associated with diminished expression level of calcium cycling proteins of the sarcoplasmic reticulum such as the ryanodine receptor, Ca2+-ATPase, calsequestrin, and triadin (but not phospholamban), as well as significantly reduced calcium uptake in microsomal fractions. These data demonstrate that SLMAP is a regulator of E-C coupling at the level of the SR and its perturbation results in progressive deterioration of cardiac electrophysiology and function.

Abstract MP216: Identification Of Novel Phosphoprotein Signaling Pathways In Human Dilated Cardiomyopathy By Integrative Proteomic And Phosphoproteomic Analysis

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Cristine J Reitz ◽  
Marjan Tavassoli ◽  
Da Hye Kim ◽  
Sina Hadipour-Lakmehsari ◽  
Saumya Shah ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Cardiac Tissue ◽  
Regulatory Element ◽  
Critical Role ◽  
Left Ventricular ◽  
Confocal Imaging ◽  
Intercalated Disc ◽  
Bioinformatics Analyses ◽  
Tissue Samples ◽  
And Function

Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure, yet the majority of the underlying signaling mechanisms remain poorly characterized. Protein phosphorylation is a key regulatory element with profound effects on the activity and function of signaling networks; however, there is a lack of comprehensive phosphoproteomic studies in human DCM patients. We assessed the hypothesis that an integrative phosphoproteomics analysis of human DCM would reveal novel phosphoprotein candidates involved in disease pathophysiology. Combined proteomic and phosphoproteomic analysis of explanted left ventricular tissue samples from DCM patients ( n =4) and non-failing controls ( n =4) identified 5,570 unique proteins with 13,624 corresponding phosphorylation sites. From these analyses, we identified αT-catenin as a unique candidate protein with a cluster of 4 significantly hyperphosphorylated sites in DCM hearts ( P <0.0001), with no change in total αT-catenin expression at the protein level. Bioinformatics analyses of human datasets and confocal imaging of human and mouse cardiac tissue show highly cardiac-enriched expression of αT-catenin, localized to the cardiomyocyte intercalated disc. High resolution 3-dimensional reconstruction shows elongated intercalated disc morphology in DCM hearts (10.07±0.76 μm in controls vs. 17.20±1.87 μm in DCM, P <0.05, n =3/group), with significantly increased colocalization of αT-catenin with the intercalated disc membrane protein N-cadherin (Pearson’s coefficient 0.55±0.04 in controls vs. 0.71±0.02 in DCM, P <0.05, n =3/group). To investigate the functional role of cardiac αT-catenin phosphorylation, we overexpressed WT protein vs. non-phosphorylatable forms based on the loci identified in DCM hearts, in adult mouse cardiomyocytes using lentiviral transduction. Confocal imaging revealed significant internalization of the phospho-null form, as compared to the prominent intercalated disc staining of the WT protein (17.78±0.79% of WT vs. 9.25±0.49% of 4A mutant, P <0.0001, n =50 cells/group). Together, these findings suggest a critical role for αT-catenin phosphorylation in maintaining cardiac intercalated disc organization in human DCM.

Ca2+-ATPase and function of sarcoplasmic reticulum during cardiac hypertrophy

1991 ◽  
Vol 261 (4) ◽  
pp. L23-L26 ◽  
Author(s):  
Dmitri Levitsky ◽  
Diane De La Bastie ◽  
Ketty Schwartz ◽  
Anne-Marie Lompré
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cardiac Hypertrophy ◽  
Calcium Ion ◽  
Adenosine Triphosphatase ◽  
State Level ◽  
Calcium Sensitivity ◽  
Left Ventricular ◽  
Pump System ◽  
Messenger Ribonucleic Acid ◽  
And Function

The properties of the calcium pump system of sarcoplasmic reticulum (SR) were studied in a series of 34 rats subjected to cardiac overload and 19 sham-operated animals. Total homogenates of left ventricle were analyzed by measuring the oxalate-supported Ca2+ uptake rate, the steady-state level of the phosphorylated intermediate of Ca2+-adenosine triphosphatase (Ca2+-ATPase) (E-P), and the amount of Ca2+-ATPase mRNA. All three parameters decreased gradually as a function of the relative left ventricular weight increase. The calcium-sensitivity curves showed that the velocity of Ca2+ transport in SR from the hypertrophied heart is diminished at low as well as optimal Ca2+2 concentrations, with the dissociation constant (Kd) value for Ca2+ unchanged from that of the control preparation. Taken together with the results presented in our recent publication (De la Bastie, Levitsky, Mercadier, Marotte, Wisnewsky, Brovkovivh, Schwartz, and Lompré, Circ. Res. 66: 554–564, 1990), these data strongly indicate that differences in the Ca2+ pump activities of SR from normal and hypertrophied rat hearts are due to quantitative rather than qualitative changes of the Ca2+-ATPase protein. calcium ion uptake; calcium ion adenosine triphosphatase messenger ribonucleic acid; cardiac hypertrophy; monoclonal antibody

Prolongation of the QT interval in heart failure occurs at low but not at high heart rates

2000 ◽  
Vol 98 (5) ◽  
pp. 603-610 ◽  
Author(s):  
P. P. DAVEY ◽  
C. BARLOW ◽  
G. HART
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Left Ventricular Hypertrophy ◽  
Qt Interval ◽  
Ventricular Hypertrophy ◽  
Left Ventricular ◽  
Qt Interval Prolongation ◽  
Qt Intervals ◽  
Ventricular Structure ◽  
And Function

Abnormal left ventricular structure and function as in, for example, left ventricular hypertrophy or chronic heart failure, is associated with sudden cardiac death and, when the ejection fraction is depressed, with prolongation of the QT interval. The dependence on heart rate of QT interval prolongation in these conditions, and the relationship of any abnormalities either to deranged autonomic nervous system function or to an adverse prognosis, has not been well studied. We therefore investigated (1) the dependence on heart rate of the QT interval, and (2) the relationship between both QT interval and the QT/heart rate slope and markers of adverse prognosis in these two conditions. The QT interval was measured at rest and during exercise in 34 subjects with heart failure, 16 subjects with left ventricular hypertrophy and 16 age-matched controls with normal left ventricular structure and function. QTc (corrected QT) intervals at rest were significantly longer in heart failure patients (471±10 ms) than in controls (421±6 ms) or in subjects with hypertrophy (420±6 ms) (P < 0.05). At peak exercise, despite the attainment of similar heart rates, the QT intervals no longer differed from each other, being 281±7 ms for controls, 296±11 ms in hypertrophy and 303±10 ms in heart failure (no significant difference). The QT/heart rate slope was significantly increased in heart failure [2.3±0.1 ms·(beats/min)-1] compared with controls [1.55±0.06 ms·(beats/min)-1] and hypertrophy [1.66±0.1 ms·(beats/min)-1] (P < 0.001). In left ventricular hypertrophy, despite animal data suggesting that QT interval prolongation should occur, no abnormalities were found in QT intervals at rest or during exercise. The QT/heart rate slope did not relate to any markers for an adverse prognosis, except that of prolongation of QT interval. Long QT intervals were associated principally with impairment of left ventricular systolic function. Our data emphasize the dynamic nature of the QT interval abnormalities found in heart failure.

Abstract P396: Noncanonical Wnt5a Increases QT Interval And Susceptibility To Ventricular Arrhythmias

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Jerry Wang ◽  
Aizhu Lu ◽  
Ying Xia ◽  
Hongwei Wang ◽  
Cagla Cimenci ◽  
...  
Keyword(s):  
Heart Failure ◽  
Action Potentials ◽  
Qt Interval ◽  
Ventricular Arrhythmias ◽  
Cardiac Electrophysiology ◽  
Critical Role ◽  
Left Ventricular ◽  
Patch Clamp Recording ◽  
Surface Ecg ◽  
Patients With Heart Failure

Background: Wnt signaling plays a critical role in both embryonic cardiogenesis and cardiac remodeling in adult heart disease. We have previously demonstrated that the canonical Wnt/β-catenin pathway inhibits cardiac sodium current, but it remains unclear whether the noncanonical Wnt pathway affects cardiac electrophysiology. Methods and Results: Western blot analysis of ventricular tissues from patients with heart failure (n=6) demonstrated a 2.3x fold increase (p<0.01) in the protein level of Wnt5a, a noncanonical Wnt ligand, as compared to healthy ventricular tissues (n=5). To investigate if Wnt5a affects cardiac electrophysiology, adenovirus expressing Wnt5a and mCherry (Ad-Wnt5a) or control adenovirus expressing mCherry only (Ad-mCherry) was injected into the left ventricular free wall of adult rat hearts. At 4-5 days after virus injection, surface ECG revealed increased QT interval (p<0.01) in Ad-Wn5a-injected rats (90.1±2.3 ms n=7, vs 72.3±2.0 ms in control Ad-mCherry rats n=7). In addition, ventricular tachycardia was induced by programmed electrical stimulation in 92% (11/12) Ad-Wnt5a hearts, but only in 22% (2/9) control Ad-mCherry hearts (p<0.01). Patch-clamp recording of isolated single ventricular myocytes demonstrated that Ad-Wnt5a myocytes exhibited marked prolongation of action potential duration (APD 90 : 273±77ms, n=5) as compared to control cells (42±12 ms, n=7, p<0.05). In addition, the prolonged action potentials in Ad-Wnt5a myocytes were associated with frequent early afterdepolarizations and delayed afterdepolarizations, two mechanisms for triggered ventricular arrhythmias. Conclusion: Wnt5a is increased in the myocardium of patients with heart failure. Viral expression of Wnt5a in rat ventricular tissue increases QT interval and ventricular arrhythmia susceptibility, which is associated with prolongation of action potentials in cardiomyocytes. This may be an important target for future therapies.

Ca2+-ATPase and function of sarcoplasmic reticulum during cardiac hypertrophy

1991 ◽  
Vol 261 (4) ◽  
pp. 23-26 ◽  
Author(s):  
Dmitri Levitsky ◽  
Diane De La Bastie ◽  
Ketty Schwartz ◽  
Anne-Marie Lompré
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Cardiac Hypertrophy ◽  
Calcium Ion ◽  
Adenosine Triphosphatase ◽  
State Level ◽  
Calcium Sensitivity ◽  
Left Ventricular ◽  
Pump System ◽  
Messenger Ribonucleic Acid ◽  
And Function

The properties of the calcium pump system of sarcoplasmic reticulum (SR) were studied in a series of 34 rats subjected to cardiac overload and 19 sham-operated animals. Total homogenates of left ventricle were analyzed by measuring the oxalate-supported Ca2+ uptake rate, the steady-state level of the phosphorylated intermediate of Ca2+-adenosine triphosphatase (Ca2+-ATPase) (E-P), and the amount of Ca2+-ATPase mRNA. All three parameters decreased gradually as a function of the relative left ventricular weight increase. The calcium-sensitivity curves showed that the velocity of Ca2+ transport in SR from the hypertrophied heart is diminished at low as well as optimal Ca2+ concentrations, with the dissociation constant (Kd) value for Ca2+ unchanged from that of the control preparation. Taken together with the results presented in our recent publication (De la Bastie, Levitsky, Mercadier, Marotte, Wisnewsky, Brovkovivh, Schwartz, and Lompré, Circ. Res. 66: 554–564, 1990), these data strongly indicate that differences in the Ca2+ pump activities of SR from normal and hypertrophied rat hearts are due to quantitative rather than qualitative changes of the Ca2+-ATPase protein. calcium ion uptake; calcium ion adenosine triphosphatase messenger ribonucleic acid; cardiac hypertrophy; monoclonal antibody

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