scholarly journals NAD(P)H oxidase subunit p47phox is elevated, and p47phox knockout prevents diaphragm contractile dysfunction in heart failure

2015 ◽  
Vol 309 (5) ◽  
pp. L497-L505 ◽  
Author(s):  
Bumsoo Ahn ◽  
Adam W. Beharry ◽  
Gregory S. Frye ◽  
Andrew R. Judge ◽  
Leonardo F. Ferreira
Keyword(s):  
Heart Failure ◽  
Knockout Mice ◽  
Contractile Function ◽  
Isometric Force ◽  
Exercise Intolerance ◽  
Contractile Dysfunction ◽  
Wild Type ◽  
Shortening Velocity ◽  
Protein Levels ◽  
Specific Source

Patients with chronic heart failure (CHF) have dyspnea and exercise intolerance, which are caused in part by diaphragm abnormalities. Oxidants impair diaphragm contractile function, and CHF increases diaphragm oxidants. However, the specific source of oxidants and its relevance to diaphragm abnormalities in CHF is unclear. The p47phox-dependent Nox2 isoform of NAD(P)H oxidase is a putative source of diaphragm oxidants. Thus, we conducted our study with the goal of determining the effects of CHF on the diaphragm levels of Nox2 complex subunits and test the hypothesis that p47phox knockout prevents diaphragm contractile dysfunction elicited by CHF. CHF caused a two- to sixfold increase ( P < 0.05) in diaphragm mRNA and protein levels of several Nox2 subunits, with p47phox being upregulated and hyperphosphorylated. CHF increased diaphragm extracellular oxidant emission in wild-type but not p47phox knockout mice. Diaphragm isometric force, shortening velocity, and peak power were decreased by 20–50% in CHF wild-type mice ( P < 0.05), whereas p47phox knockout mice were protected from impairments in diaphragm contractile function elicited by CHF. Our experiments show that p47phox is upregulated and involved in the increased oxidants and contractile dysfunction in CHF diaphragm. These findings suggest that a p47phox-dependent NAD(P)H oxidase mediates the increase in diaphragm oxidants and contractile dysfunction in CHF.

scholarly journals Role of SR Ca2+-ATPase in contractile dysfunction of myocytes in tachycardia-induced heart failure

1998 ◽  
Vol 275 (1) ◽  
pp. H31-H40 ◽  
Author(s):  
Keiko Igarashi-Saito ◽  
Hiroyuki Tsutsui ◽  
Shimako Yamamoto ◽  
Masaru Takahashi ◽  
Shintaro Kinugawa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Contractile Function ◽  
Regulatory Protein ◽  
Cyclopiazonic Acid ◽  
Contractile Dysfunction ◽  
Mrna Levels ◽  
Shortening Velocity ◽  
Atpase Gene ◽  
Intracellular Ca

Sarcoplasmic reticulum (SR) Ca2+-ATPase gene expression is reduced in the failing myocardium. However, the functional relevance of these changes to myocardial contractility is not yet established. We assessed myocardial contractile function by analyzing sarcomere motion of isolated myocytes and also quantified SR Ca2+ regulatory protein gene expression by Northern blot analysis in the same hearts obtained from 10 dogs with pacing-induced heart failure (HF; 240 beats/min, 4 wk) and 7 control dogs. Sarcomere-shortening velocity was depressed in HF myocytes, accompanied by the prolongation of intracellular Ca2+ concentration ([Ca2+]i) transient measured by indo 1 fluorescence ratio. SR Ca2+-ATPase mRNA levels (normalized to glyceraldehyde-3-phosphate dehydrogenase mRNA) were significantly depressed in HF, and calsequestrin mRNA was increased. For control and HF dogs, sarcomere-shortening velocity correlated positively with Ca2+-ATPase mRNA levels ( r = 0.73, n = 17, P < 0.01) but not with calsequestrin mRNA. Ca2+-ATPase mRNA levels were correlated with45Ca2+uptake rate by SR, which was also reduced in HF. Moreover, the inhibition of SR Ca2+-ATPase with thapsigargin or cyclopiazonic acid reproduced in normal myocytes the abnormalities observed in HF myocytes, such as depressed contractility and the prolonged [Ca2+]itransient duration. A downregulation of Ca2+-ATPase gene expression and a resultant decrease in Ca2+ uptake by SR may be responsible for the contractile dysfunction and the alterations of [Ca2+]itransient in HF.

scholarly journals Catecholamine Surges Cause Cardiomyocyte Necroptosis via a RIPK1–RIPK3-Dependent Pathway in Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Penglong Wu ◽  
Mingqi Cai ◽  
Jinbao Liu ◽  
Xuejun Wang
Keyword(s):  
Heart Failure ◽  
Cardiac Injury ◽  
Underlying Mechanism ◽  
Selective Inhibitor ◽  
Blue Dye ◽  
Wild Type ◽  
Adrenergic Stimulation ◽  
Protein Levels ◽  
Regulated Necrosis ◽  
Dependent Pathway

Background: Catecholamine surges and resultant excessive β-adrenergic stimulation occur in a broad spectrum of diseases. Excessive β-adrenergic stimulation causes cardiomyocyte necrosis, but the underlying mechanism remains obscure. Necroptosis, a major form of regulated necrosis mediated by RIPK3-centered pathways, is implicated in heart failure; however, it remains unknown whether excessive β-adrenergic stimulation-induced cardiac injury involves necroptosis. Hence, we conducted the present study to address these critical gaps.Methods and Results: Two consecutive daily injections of isoproterenol (ISO; 85 mg/kg, s.c.) or saline were administered to adult mixed-sex mice. At 24 h after the second ISO injection, cardiac area with Evans blue dye (EBD) uptake and myocardial protein levels of CD45, RIPK1, Ser166-phosphorylated RIPK1, RIPK3, and Ser345-phosphorylated MLKL (p-MLKL) were significantly greater, while Ser321-phosphorylated RIPK1 was significantly lower, in the ISO-treated than in saline-treated wild-type (WT) mice. The ISO-induced increase of EBD uptake was markedly less in RIPK3−/− mice compared with WT mice (p = 0.016). Pretreatment with the RIPK1-selective inhibitor necrostatin-1 diminished ISO-induced increases in RIPK3 and p-MLKL in WT mice and significantly attenuated ISO-induced increases of EBD uptake in WT but not RIPK3−/− mice.Conclusions: A large proportion of cardiomyocyte necrosis induced by excessive β-adrenergic stimulation belongs to necroptosis and is mediated by a RIPK1–RIPK3-dependent pathway, identifying RIPK1 and RIPK3 as potential therapeutic targets for catecholamine surges.

Preservation of cardiac function by prolonged action potentials in mice deficient of KChIP2

2015 ◽  
Vol 309 (3) ◽  
pp. H481-H489 ◽  
Author(s):  
Søren Grubb ◽  
Gary L. Aistrup ◽  
Jussi T. Koivumäki ◽  
Tobias Speerschneider ◽  
Lisa A. Gottlieb ◽  
...  
Keyword(s):  
Action Potentials ◽  
Contractile Function ◽  
Cardiac Contractility ◽  
Cardiac Contraction ◽  
Compensatory Mechanism ◽  
Wild Type ◽  
Compensatory Mechanisms ◽  
Interacting Protein ◽  
Protein Levels ◽  
Cardiac Contractile

Inherited ion channelopathies and electrical remodeling in heart disease alter the cardiac action potential with important consequences for excitation-contraction coupling. Potassium channel-interacting protein 2 (KChIP2) is reduced in heart failure and interacts under physiological conditions with both Kv4 to conduct the fast-recovering transient outward K+ current ( Ito,f) and with CaV1.2 to mediate the inward L-type Ca2+ current ( ICa,L). Anesthetized KChIP2−/− mice have normal cardiac contraction despite the lower ICa,L, and we hypothesized that the delayed repolarization could contribute to the preservation of contractile function. Detailed analysis of current kinetics shows that only ICa,L density is reduced, and immunoblots demonstrate unaltered CaV1.2 and CaVβ2 protein levels. Computer modeling suggests that delayed repolarization would prolong the period of Ca2+ entry into the cell, thereby augmenting Ca2+-induced Ca2+ release. Ca2+ transients in disaggregated KChIP2−/− cardiomyocytes are indeed comparable to wild-type transients, corroborating the preserved contractile function and suggesting that the compensatory mechanism lies in the Ca2+-induced Ca2+ release event. We next functionally probed dyad structure, ryanodine receptor Ca2+ sensitivity, and sarcoplasmic reticulum Ca2+ load and found that increased temporal synchronicity of the Ca2+ release in KChIP2−/− cardiomyocytes may reflect improved dyad structure aiding the compensatory mechanisms in preserving cardiac contractile force. Thus the bimodal effect of KChIP2 on Ito,f and ICa,L constitutes an important regulatory effect of KChIP2 on cardiac contractility, and we conclude that delayed repolarization and improved dyad structure function together to preserve cardiac contraction in KChIP2−/− mice.

scholarly journals Cardiac deletion of α-E-catenin leads to redused expression of the main component of desmosomes – γ-catenin

1970 ◽  
Vol 21 ◽  
pp. 293-296
Author(s):  
V. V. Balatskyi ◽  
L. L. Matsevych ◽  
O. O. Piven
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Western Blot ◽  
Real Time ◽  
Knockout Mice ◽  
Protein Level ◽  
Conditional Knockout ◽  
Protein Levels ◽  
Main Component ◽  
Real Time Qpcr

Aim. In our present work, we have addressed to the γ-catenin, known main component of desmosomes, expression in hearts with heterozygous and homozygous knockout of α-E-catenin gene. Methods. Alpha-E-catenin conditional knockout mice were bred with α-MHC-Cre transgenic mice. We analyze expression of γ-catenin with real time qPCR and Western blot. Results. Cardiac α-E-catenin deletion leads to downregulation of γ-catenin mRNA and protein levels only in homozygous mice, while we not observed any perturbation of γ-catenin expression in heterozygous mice. Conclusions. We have shown that homozygous knockout of α-E-catenin gene in embryonic heart occur reduction of the main component of desmosomes – γ-catenin mRNA and protein level of expression, which can lead to disruption of the desmosomes structure in adult myocardium. Keywords: α-E-catenin, heart failure, γ-catenin.

Fiber type and temperature dependence of inorganic phosphate: implications for fatigue

2004 ◽  
Vol 287 (3) ◽  
pp. C673-C681 ◽  
Author(s):  
E. P. Debold ◽  
H. Dave ◽  
R. H. Fitts
Keyword(s):  
Contractile Function ◽  
Contractile Activity ◽  
Isometric Force ◽  
Fiber Type ◽  
Type I ◽  
Type Ii ◽  
Shortening Velocity ◽  
Single Fibers ◽  
Type I Fibers ◽  
Type Ii Fibers

Elevated levels of Pi are thought to cause a substantial proportion of the loss in muscular force and power output during fatigue from intense contractile activity. However, support for this hypothesis is based, in part, on data from skinned single fibers obtained at low temperatures (≤15°C). The effect of high (30 mM) Pi concentration on the contractile function of chemically skinned single fibers was examined at both low (15°C) and high (30°C) temperatures using fibers isolated from rat soleus (type I fibers) and gastrocnemius (type II fibers) muscles. Elevating Pi from 0 to 30 mM at saturating free Ca2+ levels depressed maximum isometric force (Po) by 54% at 15°C and by 19% at 30°C ( P < 0.05; significant interaction) in type I fibers. Similarly, the Po of type II fibers was significantly more sensitive to high levels of Pi at the lower (50% decrease) vs. higher temperature (5% decrease). The maximal shortening velocity of both type I and type II fibers was not significantly affected by elevated Pi at either temperature. However, peak fiber power was depressed by 49% at 15°C but by only 16% at 30°C in type I fibers. Similarly, in type II fibers, peak power was depressed by 40 and 18% at 15 and 30°C, respectively. These data suggest that near physiological temperatures and at saturating levels of intracellular Ca2+, elevated levels of Pi contribute less to fatigue than might be inferred from data obtained at lower temperatures.

Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity

2004 ◽  
Vol 286 (3) ◽  
pp. H1146-H1153 ◽  
Author(s):  
Jo El J. Schultz ◽  
Betty J. Glascock ◽  
Sandra A. Witt ◽  
Michelle L. Nieman ◽  
Kalpana J. Nattamai ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Wild Type ◽  
Human Heart Failure ◽  
Protein Levels ◽  
Plasmic Reticulum ◽  
Lv Mass ◽  
Pump Activity

We recently developed a mouse model with a single functional allele of Serca2 ( Serca2+/–) that shows impaired cardiac contractility and relaxation without overt heart disease. The goal of this study was to test the hypothesis that chronic reduction in sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2 levels in combination with an increased hemodynamic load will result in an accelerated pathway to heart failure. Age-matched wild-type and Serca2+/– mice were subjected to 10 wk of pressure overload via transverse aortic coarctation surgery. Cardiac hypertrophy and heart failure were assessed by echocardiography, gravimetry/histology, hemodynamics, and Western blotting analyses. Our results showed that ∼64% of coarcted Serca2+/– mice were in heart failure compared with 0% of coarcted wild-type mice ( P < 0.05). Overall, morbidity and mortality were greatly increased in Serca2+/– mice under pressure overload. Echocardiography assessment revealed a significant increase in left ventricular (LV) mass, and LV hypertrophy in coarcted Serca2+/– mice converted from a concentric to an eccentric pattern, similar to that seen in human heart failure. Coarcted Serca2+/– mice had decreased contractile/systolic and relaxation/diastolic performance and/or function compared with coarcted wild-type mice ( P < 0.05), despite a similar duration and degree of pressure overload. SERCA2a protein levels were significantly reduced (>50%) in coarcted Serca2+/– mice compared with noncoarcted and coarcted wild-type mice. Our findings suggest that reduction in SERCA2 levels in combination with an increased hemodynamic load results in an accelerated pathway to heart failure.

scholarly journals Slowing of cardiomyocyte Ca2+ release and contraction during heart failure progression in postinfarction mice

2009 ◽  
Vol 296 (4) ◽  
pp. H1069-H1079 ◽  
Author(s):  
Halvor K. Mørk ◽  
Ivar Sjaastad ◽  
Ole M. Sejersted ◽  
William E. Louch
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Contractile Function ◽  
Cardiac Contractility ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Shortening Velocity ◽  
Transient Time

Deterioration of cardiac contractility during congestive heart failure (CHF) is believed to involve decreased function of individual cardiomyocytes and may include reductions in contraction magnitude and/or kinetics. We examined the progression of in vivo and in vitro alterations in contractile function in CHF mice and investigated underlying alterations in Ca2+ homeostasis. Following induction of myocardial infarction (MI), mice with CHF were examined at early (1 wk post-MI) and chronic (10 wk post-MI) stages of disease development. Sham-operated mice served as controls. Global and local left ventricle function were assessed by echocardiography in sedated animals (∼2% isoflurane). Excitation-contraction coupling was examined in cardiomyocytes isolated from the viable septum. CHF progression between 1 and 10 wk post-MI resulted in increased mortality, development of hypertrophy, and deterioration of global left ventricular function. Local function in the noninfarcted myocardium also declined, as posterior wall shortening velocity was reduced in chronic CHF (1.2 ± 0.1 vs. 1.9 ± 0.2 cm/s in sham). Parallel alterations occurred in isolated cardiomyocytes since contraction and Ca2+ transient time to peak values were prolonged in chronic CHF (115 ± 6 and 158 ± 11% sham values, respectively). Surprisingly, contraction and Ca2+ transient magnitudes in CHF were larger than sham values at both time points, resulting from increased sarcoplasmic reticulum Ca2+ content and greater Ca2+ influx via L-type channels. We conclude that, in mice with CHF following myocardial infarction, declining myocardial function involves slowing of cardiomyocyte contraction without reduction in contraction magnitude. Corresponding alterations in Ca2+ transients suggest that slowing of Ca2+ release is a critical mediator of CHF progression.

scholarly journals Selective Connexin43 Inhibition Prevents Isoproterenol-Induced Arrhythmias and Lethality in Muscular Dystrophy Mice

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
J. Patrick Gonzalez ◽  
Jayalakshmi Ramachandran ◽  
Lai-Hua Xie ◽  
Jorge E. Contreras ◽  
Diego Fraidenraich
Keyword(s):  
Heart Failure ◽  
Muscular Dystrophy ◽  
Selective Inhibition ◽  
Cardiac Conduction ◽  
Peptide Mimetics ◽  
Wild Type ◽  
Protein Levels ◽  
Junction Protein ◽  
Life Threatening ◽  
Gap Junction Protein

Abstract Duchenne muscular dystrophy (DMD) is caused by an X-linked mutation that leads to the absence of dystrophin, resulting in life-threatening arrhythmogenesis and associated heart failure. We targeted the gap junction protein connexin43 (Cx43) responsible for maintaining cardiac conduction. In mild mdx and severe mdx:utr mouse models of DMD and human DMD tissues, Cx43 was found to be pathologically mislocalized to lateral sides of cardiomyocytes. In addition, overall Cx43 protein levels were markedly increased in mouse and human DMD heart tissues examined. Electrocardiography on isoproterenol challenged mice showed that both models developed arrhythmias and died within 24 hours, while wild-type mice were free of pathology. Administering peptide mimetics to inhibit lateralized Cx43 function prior to challenge protected mdx mice from arrhythmogenesis and death, while mdx:utr mice displayed markedly improved ECG scores. These findings suggest that Cx43 lateralization contributes significantly to DMD arrhythmogenesis and that selective inhibition may provide substantial benefit.

scholarly journals Vitamin D signaling pathway plays an important role in the development of heart failure after myocardial infarction

2013 ◽  
Vol 114 (8) ◽  
pp. 979-987 ◽  
Author(s):  
Soochan Bae ◽  
Sylvia S. Singh ◽  
Hyeon Yu ◽  
Ji Yoo Lee ◽  
Byung Ryul Cho ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Vitamin D ◽  
Cardiac Function ◽  
Significant Decline ◽  
Vehicle Group ◽  
Wild Type ◽  
Protein Levels ◽  
Vitamin D Analog ◽  
Vitamin D Signaling

Accumulating evidence suggests that vitamin D deficiency plays a crucial role in heart failure. However, whether vitamin D signaling itself plays an important role in cardioprotection is poorly understood. In this study, we examined the mechanism of modulating vitamin D signaling on progression to heart failure after myocardial infarction (MI) in mice. Vitamin D signaling was activated by administration of paricalcitol (PC), an activated vitamin D analog. Wild-type (WT) mice underwent sham or MI surgery and then were treated with either vehicle or PC. Compared with vehicle group, PC attenuated development of heart failure after MI associated with decreases in biomarkers, apoptosis, inflammation, and fibrosis. There was also improvement of cardiac function with PC treatment after MI. Furthermore, vitamin D receptor (VDR) mRNA and protein levels were restored by PC treatment. Next, to explore whether defective vitamin D signaling exhibited deleterious responses after MI, WT and VDR knockout (KO) mice underwent sham or MI surgery and were analyzed 4 wk after MI. VDR KO mice displayed a significant decline in survival rate and cardiac function compared with WT mice after MI. VDR KO mice also demonstrated a significant increase in heart failure biomarkers, apoptosis, inflammation, and fibrosis. Vitamin D signaling promotes cardioprotection after MI through anti-inflammatory, antifibrotic and antiapoptotic mechanisms.

scholarly journals Deficiency of selenoprotein S, an endoplasmic reticulum resident oxidoreductase, impairs the contractile function of fast-twitch hindlimb muscles

2018 ◽  
Vol 315 (2) ◽  
pp. R380-R396 ◽  
Author(s):  
Alex B. Addinsall ◽  
Craig R. Wright ◽  
Chris S. Shaw ◽  
Natasha L. McRae ◽  
Leonard G. Forgan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Knockout Mice ◽  
Contractile Function ◽  
Whole Body ◽  
Force Frequency ◽  
Wild Type ◽  
Selenoprotein S ◽  
Hindlimb Muscles ◽  
Fast Twitch

Selenoprotein S (Seps1) is an endoplasmic reticulum (ER) resident antioxidant implicated in ER stress and inflammation. In human vastus lateralis and mouse hindlimb muscles, Seps1 localization and expression were fiber-type specific. In male Seps1+/− heterozygous mice, spontaneous physical activity was reduced compared with wild-type littermates ( d = 1.10, P = 0.029). A similar trend was also observed in Seps1−/− knockout mice ( d = 1.12, P = 0.051). Whole body metabolism, body composition, extensor digitorum longus (EDL), and soleus mass and myofiber diameter were unaffected by genotype. However, in isolated fast EDL muscles from Seps1−/− knockout mice, the force frequency curve (FFC; 1–120 Hz) was shifted downward versus EDL muscles from wild-type littermates ( d = 0.55, P = 0.002), suggestive of reduced strength. During 4 min of intermittent, submaximal (60 Hz) stimulation, the genetic deletion or reduction of Seps1 decreased EDL force production ( d = 0.52, P < 0.001). Furthermore, at the start of the intermittent stimulation protocol, when compared with the 60-Hz stimulation of the FFC, EDL muscles from Seps1−/− knockout or Seps1+/− heterozygous mice produced 10% less force than those from wild-type littermates ( d = 0.31, P < 0.001 and d = 0.39, P = 0.015). This functional impairment was associated with reduced mRNA transcript abundance of thioredoxin-1 ( Trx1), thioredoxin interacting protein ( Txnip), and the ER stress markers Chop and Grp94, whereas, in slow soleus muscles, Seps1 deletion did not compromise contractile function and Trx1 ( d = 1.38, P = 0.012) and Txnip ( d = 1.27, P = 0.025) gene expression was increased. Seps1 is a novel regulator of contractile function and cellular stress responses in fast-twitch muscles.

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