scholarly journals Organization of β-adrenoceptor signaling compartments by sympathetic innervation of cardiac myocytes

2007 ◽  
Vol 176 (4) ◽  
pp. 521-533 ◽  
Author(s):  
Olga G. Shcherbakova ◽  
Carl M. Hurt ◽  
Yang Xiang ◽  
Mark L. Dell'Acqua ◽  
Qi Zhang ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Myocytes ◽  
Contractile Function ◽  
Sympathetic Neurons ◽  
Sympathetic Innervation ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Specific Regulation

The sympathetic nervous system regulates cardiac function through the activation of adrenergic receptors (ARs). β1 and β2ARs are the primary sympathetic receptors in the heart and play different roles in regulating cardiac contractile function and remodeling in response to injury. In this study, we examine the targeting and trafficking of β1 and β2ARs at cardiac sympathetic synapses in vitro. Sympathetic neurons form functional synapses with neonatal cardiac myocytes in culture. The myocyte membrane develops into specialized zones that surround contacting axons and contain accumulations of the scaffold proteins SAP97 and AKAP79/150 but are deficient in caveolin-3. The β1ARs are enriched within these zones, whereas β2ARs are excluded from them after stimulation of neuronal activity. The results indicate that specialized signaling domains are organized in cardiac myocytes at sites of contact with sympathetic neurons and that these domains are likely to play a role in the subtype-specific regulation of cardiac function by β1 and β2ARs in vivo.

scholarly journals FTO-Dependent N 6 -Methyladenosine Regulates Cardiac Function During Remodeling and Repair

Circulation ◽  
2019 ◽  
Vol 139 (4) ◽  
pp. 518-532 ◽  
Author(s):  
Prabhu Mathiyalagan ◽  
Marta Adamiak ◽  
Joshua Mayourian ◽  
Yassine Sassi ◽  
Yaxuan Liang ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Mouse Models ◽  
Contractile Function ◽  
Cardiac Contraction ◽  
Functional Importance ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Rna Immunoprecipitation

Background: Despite its functional importance in various fundamental bioprocesses, studies of N 6 -methyladenosine (m6A) in the heart are lacking. Here, we show that the FTO (fat mass and obesity-associated protein), an m6A demethylase, plays a critical role in cardiac contractile function during homeostasis, remodeling, and regeneration. Methods: We used clinical human samples, preclinical pig and mouse models, and primary cardiomyocyte cell cultures to study the functional role of m6A and FTO in the heart and in cardiomyocytes. We modulated expression of FTO by using adeno-associated virus serotype 9 (in vivo), adenovirus (both in vivo and in vitro), and small interfering RNAs (in vitro) to study its function in regulating cardiomyocyte m6A, calcium dynamics and contractility, and cardiac function postischemia. We performed methylated (m6A) RNA immunoprecipitation sequencing to map transcriptome-wide m6A, and methylated (m6A) RNA immunoprecipitation quantitative polymerase chain reaction assays to map and validate m6A in individual transcripts, in healthy and failing hearts, and in myocytes. Results: We discovered that FTO has decreased expression in failing mammalian hearts and hypoxic cardiomyocytes, thereby increasing m6A in RNA and decreasing cardiomyocyte contractile function. Improving expression of FTO in failing mouse hearts attenuated the ischemia-induced increase in m6A and decrease in cardiac contractile function. This is performed by the demethylation activity of FTO, which selectively demethylates cardiac contractile transcripts, thus preventing their degradation and improving their protein expression under ischemia. In addition, we demonstrate that FTO overexpression in mouse models of myocardial infarction decreased fibrosis and enhanced angiogenesis. Conclusions: Collectively, our study demonstrates the functional importance of the FTO-dependent cardiac m6A methylome in cardiac contraction during heart failure and provides a novel mechanistic insight into the therapeutic mechanisms of FTO.

Mast cell stabilization improves cardiac contractile function following hemorrhagic shock and resuscitation

2008 ◽  
Vol 294 (6) ◽  
pp. H2456-H2464 ◽  
Author(s):  
David J. Santone ◽  
Rohan Shahani ◽  
Barry B. Rubin ◽  
Alex D. Romaschin ◽  
Thomas F. Lindsay
Keyword(s):  
Mast Cell ◽  
Cardiac Function ◽  
Hemorrhagic Shock ◽  
Contractile Function ◽  
Systolic Pressure ◽  
Histological Evaluation ◽  
Sprague Dawley ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile

Hemorrhagic shock (HS) is associated with cardiac contractile dysfunction. Mast cell (MC) degranulation is hypothesized to mediate the cardiodepressant effect. Cardiac function was assessed after HS and resuscitation (HS/R) with the administration of the MC stabilizers to prevent MC degranulation. Anesthetized male Sprague-Dawley rats were randomized to sham-operated control or HS/R groups and underwent 60 min of HS followed by 2 h of resuscitated reperfusion. Animals in the HS/R groups were randomized to receive cromolyn (5 mg/kg), ketotifen (1 mg/kg), or saline 15 min before shock. Hearts were excised following HS or 2 h of reperfusion, and function was assessed on a Langendorff apparatus. A second group of randomized animals had serial blood samples taken to assess MC degranulation by quantifying levels of serum β-hexosaminidase. Hearts were excised at 0 min (before HS) and following 60 min of HS (before resuscitation) for a histological evaluation of MC density and degranulation. In vivo MC stabilization using ketotifen and cromolyn improved cardiac peak systolic pressure ( P < 0.05), contractility ( P < 0.05), and relaxation ( P < 0.05) compared with that of HS controls. Serum β-hexosaminidase increased during HS/R and was inhibited by MC stabilization ( P < 0.05). Degranulation was inhibited when assessed by histochemistry and immune fluorescence. The inhibition of MC degranulation can significantly improve cardiac function following HS/R.

Lipid peroxidation contributes to cardiac deficits after ischemia and reperfusion of the small bowel

1993 ◽  
Vol 264 (5) ◽  
pp. H1686-H1692 ◽  
Author(s):  
J. W. Horton ◽  
D. J. White
Keyword(s):  
Lipid Peroxidation ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Cardiac Contractile Function ◽  
Langendorff Preparation ◽  
Cardiac Contractile ◽  
Intestinal Ischemia Reperfusion

Our previous studies showed that intestinal ischemia-reperfusion (IR) impairs cardiac contractile function. The present study examined the contribution of oxygen free radicals and lipid peroxidation of cardiac cell membrane to cardiac dysfunction after intestinal IR in a rat model of superior mesenteric artery (SMA) occlusion (atraumatic clip for 20 min) and collateral arcade ligation. Controls were sham operated (group 1, n = 25). In group 2, 30 rats with SMA occlusion were killed 3-4 h after reperfusion without treatment. Aminosteroid (U-74389F), a pharmacological agent known to inhibit lipid peroxidation of membranes, was given 1 min before occlusion of the SMA (group 3, n = 19). All rats were killed 3-4 h after reperfusion of the ischemic intestine, and the hearts were harvested for in vitro assessment of cardiac function (Langendorff preparation). Cardiac contractile depression occurred in the untreated group as indicated by a fall in left ventricular pressure (from 76 +/- 3 to 64 +/- 3 mmHg, P = 0.01), maximum +dP/dt (from 1,830 +/- 60 to 1,577 +/- 64 mmHg/s, P = 0.05), and maximum -dP/dt (from 1,260 +/- 50 to 950 +/- 60 mmHg/s, P = 0.005). Lipid peroxidation of cardiac membranes occurred after untreated IR as indicated by the rise in cardiac malondialdehyde levels (MDA) (from 0.203 +/- 0.046 to 0.501 +/- 0.044 nM/mg protein, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Concurrent opposite effects of trichostatin A, an inhibitor of histone deacetylases, on expression of α-MHC and cardiac tubulins: implication for gain in cardiac muscle contractility

2005 ◽  
Vol 288 (3) ◽  
pp. H1477-H1490 ◽  
Author(s):  
Francesca J. Davis ◽  
Jyothish B Pillai ◽  
Madhu Gupta ◽  
Mahesh P. Gupta
Keyword(s):  
Cardiac Myocytes ◽  
Histone Deacetylases ◽  
Contractile Function ◽  
Trichostatin A ◽  
In Vivo Model ◽  
Ang Ii ◽  
Cardiac Contractile Function ◽  
Noticeable Effect

Histone deacetylases (HDACs) are a family of enzymes that catalyze the removal of acetyl groups from core histones, resulting in change of chromatin structure and gene transcription activity. In the heart, HDACs are targets of hypertrophic signaling, and their nonspecific inhibition by trichostatin A (TSA) attenuates hypertrophy of cultured cardiac myocytes. In this study, we examined the effect of TSA on two major determinants of cardiac contractility: α-myosin heavy chain (MHC) expression and microtubular composition and organization. TSA upregulated the expression of α-MHC in cultured cardiac myocytes, as well as in an in vivo model of hypothyroid rats. Studies designed to delineate mechanisms of α-MHC induction by TSA revealed an obligatory role of early growth response factor-1 on activation of the α-MHC promoter. Concurrently, TSA downregulated the expression of α- and β-tubulins and prevented the induction of tubulins by a hypertrophy agonist, ANG II. The ANG II-mediated increased proportion of α- and β-tubulins associated with polymerized microtubules was also markedly reduced after treatment of cells by TSA. Results obtained from immunofluorescent microscopy indicated that TSA had no noticeable effect on the organization of cardiac microtubules in control cells, whereas it prevented the ANG II-induced dense parallel linear arrays of microtubules to a profile similar to that of controls. Together, these results demonstrate that inhibition of HDACs by TSA regulates the cardiac α-MHC and tubulins in a manner predictive of improved cardiac contractile function. These studies improve our understanding of the role of HDACs on cardiac hypertrophy with implications in development of new therapeutic agents for treatment of cardiac abnormalities.

Hypoxic pHi and function modulation by Na+/H+ exchange and alpha-adrenoreceptor inhibition in heart in vivo

1997 ◽  
Vol 272 (6) ◽  
pp. H2664-H2670 ◽  
Author(s):  
M. A. Portman ◽  
Y. Xiao ◽  
B. G. Broers ◽  
X. H. Ning
Keyword(s):  
Cardiac Function ◽  
Contractile Function ◽  
High Energy ◽  
Left Ventricular ◽  
Resonance Spectroscopy ◽  
Cardiac Contractile Function ◽  
Significant Drop ◽  
And Function ◽  
Phi Regulation

Regulation of intracellular pH (pHi) may contribute to maintenance of cardiac contractile function during graded hypoxia in vivo. To test this hypothesis, we disturbed pHi regulation in vivo using two approaches: alpha-adrenoreceptor antagonism with phentolamine (1 mg/kg) (Phen; n = 9); and Na+/H+ exchange inhibition with HOE-642 (2 mg/kg; n = 6) before graded hypoxia in open-chest sheep. Hemodynamic parameters including left ventricular maximal pressure development (dP/dtmax) cardiac index (CI), and left ventricular power were monitored continuously and simultaneously with high-energy phosphate levels and pHi, measured with 31P nuclear magnetic resonance spectroscopy in Phen, HOE-642, and control (Con; n = 9). In subgroups (n = 6) in Con and Phen, coronary flow, myocardial oxygen consumption (MVO2), and lactate uptake were also measured. During hypoxia, the functional parameters left ventricular dP/dtmax, CI, and left ventricular power decreased significantly compared with baseline and Con values. These decreases were preceded by a significant drop (P < 0.05) in pHi from 7.10 +/- 0.04 to 6.69 +/- 0.05 in Phen and corresponded temporally to a pHi drop from 7.10 +/- 0.02 to 6.77 +/- 0.03 in HOE-642. Decreases in pHi in Phen were not preceded by decreases in cardiac function or MVO2. In contrast, cardiac function parameters increased significantly in Con, whereas no significant pHi decrease occurred (7.07 +/- 0.03 to 6.98 +/- 0.04). We conclude that these data indicate that pHi regulation can be disrupted through alpha-adrenergic antagonism or Na+/H(+)-exchange inhibition in vivo. These studies demonstrate that pHi regulation performs a role in the modulation of cardiac function during hypoxia in vivo.

scholarly journals Redox-Active Drug, MnTE-2-PyP5+, Prevents and Treats Cardiac Arrhythmias Preserving Heart Contractile Function

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Andrezza M. Barbosa ◽  
José F. Sarmento-Neto ◽  
José E. R. Menezes Filho ◽  
Itamar C. G. Jesus ◽  
Diego S. Souza ◽  
...  
Keyword(s):  
Cardiac Arrhythmias ◽  
Contractile Function ◽  
Antiarrhythmic Effect ◽  
Cardiac Contractile Function ◽  
Rat Cardiomyocytes ◽  
Cell Contractility ◽  
Redox Active ◽  
Intracellular Ca

Background. Cardiomyopathies remain among the leading causes of death worldwide, despite all efforts and important advances in the development of cardiovascular therapeutics, demonstrating the need for new solutions. Herein, we describe the effects of the redox-active therapeutic Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, AEOL10113, BMX-010 (MnTE-2-PyP5+), on rat heart as an entry to new strategies to circumvent cardiomyopathies. Methods. Wistar rats weighing 250-300 g were used in both in vitro and in vivo experiments, to analyze intracellular Ca2+ dynamics, L-type Ca2+ currents, Ca2+ spark frequency, intracellular reactive oxygen species (ROS) levels, and cardiomyocyte and cardiac contractility, in control and MnTE-2-PyP5+-treated cells, hearts, or animals. Cells and hearts were treated with 20 μM MnTE-2-PyP5+ and animals with 1 mg/kg, i.p. daily. Additionally, we performed electrocardiographic and echocardiographic analysis. Results. Using isolated rat cardiomyocytes, we observed that MnTE-2-PyP5+ reduced intracellular Ca2+ transient amplitude, without altering cell contractility. Whereas MnTE-2-PyP5+ did not alter basal ROS levels, it was efficient in modulating cardiomyocyte redox state under stress conditions; MnTE-2-PyP5+ reduced Ca2+ spark frequency and increased sarcoplasmic reticulum (SR) Ca2+ load. Accordingly, analysis of isolated perfused rat hearts showed that MnTE-2-PyP5+ preserves cardiac function, increases SR Ca2+ load, and reduces arrhythmia index, indicating an antiarrhythmic effect. In vivo experiments showed that MnTE-2-PyP5+ treatment increased Ca2+ transient, preserved cardiac ejection fraction, and reduced arrhythmia index and duration. MnTE-2-PyP5+ was effective both to prevent and to treat cardiac arrhythmias. Conclusion. MnTE-2-PyP5+ prevents and treats cardiac arrhythmias in rats. In contrast to most antiarrhythmic drugs, MnTE-2-PyP5+ preserves cardiac contractile function, arising, thus, as a prospective therapeutic for improvement of cardiac arrhythmia treatment.

Taxol, a Microtubule Stabilizer, Improves Cardiac Contractile Function during Ischemia in vitro

Pharmacology ◽  
2010 ◽  
Vol 85 (5) ◽  
pp. 301-310 ◽  
Author(s):  
Junjie Xiao ◽  
Hong Zhao ◽  
Dandan Liang ◽  
Ying Liu ◽  
Hong Zhang ◽  
...  
Keyword(s):  
Contractile Function ◽  
Cardiac Contractile Function ◽  
Cardiac Contractile ◽  
Microtubule Stabilizer

In vitro endotoxin exposure induces contractile dysfunction in adult rat cardiac myocytes

1994 ◽  
Vol 267 (5) ◽  
pp. H1745-H1752 ◽  
Author(s):  
S. Tao ◽  
T. M. McKenna
Keyword(s):  
Nitric Oxide ◽  
Cardiac Myocytes ◽  
Contractile Function ◽  
Relaxation Times ◽  
Cardiac Cells ◽  
Cyclic Monophosphate ◽  
Adult Rat ◽  
Endotoxin Exposure

In vivo endotoxin treatment causes a nitric oxide-mediated hypocontractility in cardiac myocytes. The objective of this study was to assess whether in vitro endotoxin exposure confers similar contractile defects in adult rat cardiac cells. We found that incubation of cardiac myocytes for 6 h with 10-100 ng/ml endotoxin resulted in progressive time- and protein synthesis-dependent decreases in electrically stimulated twitch magnitudes and increased contraction and relaxation times. Serum was not required for the endotoxin-induced hypocontractility. The endotoxin-induced defect in contractility was reversed over time, since myocytes continuously incubated with endotoxin for 24 h exhibited normal contractility; in contrast, control cells incubated for 18 h were suppressed by a subsequent 6-h exposure to endotoxin. Nitric oxide synthase activity was increased after a 6-h endotoxin treatment as evidenced by a dose-dependent enhanced conversion of [3H]arginine to [3H]citrulline and by elevated guanosine 3',5'-cyclic monophosphate levels. Superfusion of endotoxin-incubated cells with N omega-nitro-L-arginine methyl ester restored contractile function, whereas superfusion with L-arginine reimposed abnormal contractility. Naive myocytes superfused with 8-bromoguanosine 3',5'-cyclic monophosphate expressed contractile defects similar to those induced by endotoxin. These findings demonstrate that endotoxin has direct negative effects on cardiac cell contractile function and that induction of NO synthase activity is a primary intracellular mediator of the diminished contractility.

Involvement of vitamin D3 with cardiovascular function. II. Direct and indirect effects

1987 ◽  
Vol 253 (6) ◽  
pp. E675-E683 ◽  
Author(s):  
R. E. Weishaar ◽  
R. U. Simpson
Keyword(s):  
Serum Calcium ◽  
Vitamin D3 ◽  
Contractile Function ◽  
Initial Period ◽  
Cardiovascular Function ◽  
Cardiac Contractile Function ◽  
Deficient Diet ◽  
Cardiac Contractile ◽  
Vitamin D3 Deficiency

To determine whether the changes in cardiovascular function that accompany vitamin D3 deficiency are the direct result of hypovitaminosis D3 or a response to the hypocalcemia that accompanies vitamin D3 deficiency, rats were maintained for 9 wk on a vitamin D3-deficient diet containing either low (0.4%) calcium or high (2.5%) calcium to prevent hypocalcemia. Rats were also maintained on the low-calcium, vitamin D3-deficient diet for 9 wk and then transferred to diets designed to reverse hypocalcemia or vitamin D3 deficiency. The results demonstrate that the changes in in vitro cardiac contractile function that accompany vitamin D3 deficiency 1) could not be prevented by preventing the hypocalcemia that normally accompanies vitamin D3 depletion or 2) could not be reversed by restoration of serum calcium to normal levels after the initial period of vitamin D3 depletion. In contrast, the change in in vitro vascular muscle contractile function observed in vitamin D3-deficient, hypocalcemic rats could be prevented by maintaining serum calcium at normal levels and also reversed by restoration of serum calcium to normal after an initial period of vitamin D3 deficiency. These observations indicate that hypocalcemia does not account for the changes in cardiac contractile function that result from vitamin D3 depletion and suggest a direct role for vitamin D3 or its metabolite 1,25-dihydroxyvitamin D3 in regulating cardiac contractility. Possible mechanisms underlying this direct effect were also explored.

scholarly journals Cardiomyocyte-specific overexpression of an active form of Rac predisposes the heart to increased myocardial stunning and ischemia-reperfusion injury

2013 ◽  
Vol 304 (2) ◽  
pp. H294-H302 ◽  
Author(s):  
M. A. Hassan Talukder ◽  
Mohammad T. Elnakish ◽  
Fuchun Yang ◽  
Yoshinori Nishijima ◽  
Mazin A. Alhaj ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Ischemia Reperfusion Injury ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Active Form ◽  
Mutant Form ◽  
Cardiac Contractile Function ◽  
The Impact

The GTP-binding protein Rac regulates diverse cellular functions including activation of NADPH oxidase, a major source of superoxide production (O2·−). Rac1-mediated NADPH oxidase activation is increased after myocardial infarction (MI) and heart failure both in animals and humans; however, the impact of increased myocardial Rac on impending ischemia-reperfusion (I/R) is unknown. A novel transgenic mouse model with cardiac-specific overexpression of constitutively active mutant form of Zea maize Rac D (ZmRacD) gene has been reported with increased myocardial Rac-GTPase activity and O2·− generation. The goal of the present study was to determine signaling pathways related to increased myocardial ZmRacD and to what extent hearts with increased ZmRacD proteins are susceptible to I/R injury. The effect of myocardial I/R was examined in young adult wild-type (WT) and ZmRacD transgenic (TG) mice. In vitro reversible myocardial I/R for postischemic cardiac function and in vivo regional myocardial I/R for MI were performed. Following 20-min global ischemia and 45-min reperfusion, postischemic cardiac contractile function and heart rate were significantly reduced in TG hearts compared with WT hearts. Importantly, acute regional myocardial I/R (30-min ischemia and 24-h reperfusion) caused significantly larger MI in TG mice compared with WT mice. Western blot analysis of cardiac homogenates revealed that increased myocardial ZmRacD gene expression is associated with concomitant increased levels of NADPH oxidase subunit gp91phox, O2·−, and P21-activated kinase. Thus these findings provide direct evidence that increased levels of active myocardial Rac renders the heart susceptible to increased postischemic contractile dysfunction and MI following acute I/R.

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