Regional myocardial perfusion under exchange transfusion with liposomal hemoglobin: in vivo and in vitro studies using rat hearts

2005 ◽  
Vol 288 (4) ◽  
pp. H1909-H1914 ◽  
Author(s):  
T. Matsumoto ◽  
T. Asano ◽  
K. Mano ◽  
H. Tachibana ◽  
M. Todoh ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Coronary Flow ◽  
Exchange Transfusion ◽  
Volume Fraction ◽  
Left Ventricular ◽  
Rat Hearts ◽  
Coronary Tone ◽  
Carotid Flow

The purpose of this study was to test the hypothesis that exchange transfusion with liposomal hemoglobin (LH) reduces the microheterogeneity of regional myocardial flows while sustaining cardiac function. Neo Red Cell mixed with albumin was used as the LH solution, in which the LH volume fraction was 17∼18% and hemoglobin density was nearly two-thirds smaller than in rat blood. Regional myocardial flows in left ventricular free walls were measured by tracer digitalradiography (100-μm resolution) in anesthetized rats with or without 50% blood-LH exchange transfusion. Within-layer flow distributions showed lower heterogeneity with ( n = 8) than without ( n = 8) LH transfusion. No extravasation of hemoglobin was confirmed by 3,3-diaminobenzidin staining ( n = 2). Carotid flow increased by 68% due to LH transfusion, whereas arterial pressure and heart rate remained unchanged. On the other hand, cross-circulated rat hearts ( n = 7) were used to evaluate the effects of 50% blood-LH exchange on coronary flow and tone preservation under 300-beats/min pacing and 100-mmHg perfusion pressure. Blood-LH exchange caused a 71% increase of coronary flow and 10% decrease of percent flow increase during hyperemia after 30-s flow interruption. Myocardial O2 supply and consumption increased by 9% and 10%, respectively, whereas myocardial O2 extraction remained unchanged. The large increases of in vivo carotid flow and coronary flow in cross-circulated hearts due to LH coperfusion could be explained by the reduction of apparent flow viscosity. These results suggest that under LH coperfusion, the microheterogeneity of myocardial flows decreases with increased coronary flow while fairly preserving coronary tone and cardiac function.

Abstract 5402: Two Photon Microscopy Measurements Of Sub-epicardial Sarcomere Length In Perfused Rat Hearts

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Patrizia Camelliti ◽  
Gil Bub ◽  
Daniel J Stuckey ◽  
Christian Bollensdorff ◽  
Damian J Tyler ◽  
...  
Keyword(s):  
Sarcomere Length ◽  
Left Ventricular ◽  
Model Systems ◽  
Future Research ◽  
Fundamental Parameter ◽  
Rat Hearts ◽  
Perfused Hearts ◽  
Over Time

Sarcomere length (SL) is a fundamental parameter underlying the Frank Starling relation in the heart, as it offers an absolute representation of myocardial stretch. Previous studies addressed the Frank Starling relation by measuring SL in isolated myocytes or muscle strips. Here, we report first data obtained using a novel technique to measure sub-epicardial SL in perfused hearts. Rat hearts were Langendorff perfused (normal Tyrode solution) at a constant pressure of 90mmHg, labeled with the fluorescent membrane marker di-4-ANEPPS, and then arrested with high-K + Tyrode for either 2-photon microscopy (n=4) or MRI (n=4). Image analysis software was developed to extract SL at the cell level from >1,400 2-photon images (Fig 1 ) and correct for cell angle. SL increased by 10±2 % between 30 and 80 min of perfusion (1.98±0.04 to 2.17±0.03 μm; p<0.05; Fig 1 ). Measurements of left ventricular myocardial volume (LVMV) were made in vivo and in perfused hearts using 3D MRI. LVMV increased by 24±7% from in vivo to 30 min of perfusion, and by 11±3 % between 30 and 90 min (539±35; 664±44; 737±49 mm 3 , respectively; p<0.05; Fig 1 ). We show that SL can be measured in isolated perfused hearts. The method allowed monitoring of changes in SL over time, and showed that SL and LVMV increase to a similar extent during 30–80 min perfusion with crystalloid solution, probably due to tissue oedema. This result, together with the increase in LVMV during the first 30 min, highlights the pronounced differences between in vivo , in situ , and in vitro model systems for studies of cardiac physiology and mechanics. Future research will compare changes in SL in healthy hearts and disease models involving contractile dysfunction. Figure 1: Left: 2-photon microscopy image of di-4-ANEPPS labeled myocardium. Right: SL and LVMV changes over time.

scholarly journals Pharmacological priming of adipose-derived stem cells promotes myocardial repair

2016 ◽  
Vol 64 (1) ◽  
pp. 50-62 ◽  
Author(s):  
Jana S Burchfield ◽  
Ashley L Paul ◽  
Vishy Lanka ◽  
Wei Tan ◽  
Yongli Kong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cardiac Function ◽  
Functional Recovery ◽  
Cardiac Myocyte ◽  
Left Ventricular ◽  
Adipose Derived Stem Cells ◽  
Myocardial Repair ◽  
Myocyte Differentiation

Adipose-derived stem cells (ADSCs) have myocardial regeneration potential, and transplantation of these cells following myocardial infarction (MI) in animal models leads to modest improvements in cardiac function. We hypothesized that pharmacological priming of pre-transplanted ADSCs would further improve left ventricular functional recovery after MI. We previously identified a compound from a family of 3,5-disubstituted isoxazoles, ISX1, capable of activating an Nkx2-5-driven promoter construct. Here, using ADSCs, we found that ISX1 (20 mM, 4 days) triggered a robust, dose-dependent, fourfold increase in Nkx2-5 expression, an early marker of cardiac myocyte differentiation and increased ADSC viability in vitro. Co-culturing neonatal cardiomyocytes with ISX1-treated ADSCs increased early and late cardiac gene expression. Whereas ISX1 promoted ADSC differentiation toward a cardiogenic lineage, it did not elicit their complete differentiation or their differentiation into mature adipocytes, osteoblasts, or chondrocytes, suggesting that re-programming is cardiomyocyte specific. Cardiac transplantation of ADSCs improved left ventricular functional recovery following MI, a response which was significantly augmented by transplantation of ISX1- pretreated cells. Moreover, ISX1-treated and transplanted ADSCs engrafted and were detectable in the myocardium 3 weeks following MI, albeit at relatively small numbers. ISX1 treatment increased histone acetyltransferase (HAT) activity in ADSCs, which was associated with histone 3 and histone 4 acetylation. Finally, hearts transplanted with ISX1-treated ADSCs manifested significant increases in neovascularization, which may account for the improved cardiac function. These findings suggest that a strategy of drug-facilitated initiation of myocyte differentiation enhances exogenously transplanted ADSC persistence in vivo, and consequent tissue neovascularization, to improve cardiac function.

Abstract MP234: Novel Mybpc3 Variant Disrupts Myosin S2 Binding And Induces Heart Failure

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Taejeong Song ◽  
Rohit Singh ◽  
Darshini Desai ◽  
Sheryl E Koch ◽  
Jack Rubinstein ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Striated Muscle ◽  
Solid Phase ◽  
South Asians ◽  
Lipid Peroxide ◽  
Ventricular Volume ◽  
Left Ventricular ◽  
Heart Weight

Rationale: Cardiac m yosin binding protein-C regulates a ctomyosin interaction in striated muscle, but mutations in the MYBPC3 gene can lead to hypertrophic cardiomyopathy (HCM) as seen in some South Asians living in the USA carrying a novel variant wherein an aspartic acid is mutated to a valine at position 389 (D389V). Individuals and iPSC-derived cardiomyocytes carrying D389V display hypercontractility, indicating early onset of HCM. However, the mechanisms underlying the pathophysiology of this mutant in the context of HCM are unknown. Objective: To define the pathophysiological consequences D389V on myosin and cardiac function in vivo . Methods and Results: Compared with wild-type controls, our D389V knock-in homozygous mouse model showed decreased cardiac function by percentage of ejection fraction (-23%, P<0.01), but increased systolic left ventricular volume (+39%, P<0.01) at 3 and 6 months of age. Heart weight to tibia length ratio was significantly increased (+ 15%, P=0.05), demonstrating distinct pathogenicity. Using recombinant proteins carrying D389V substitution at the N-terminal MYBPC3 domains (rC0C2 D389V ), cosedimentation and solid-phase binding assays showed significantly reduced binding rate of rC0C2 D389V to the myosin S2 region (-55% and -23%, P<0.05, respectively), but in vitro actin motility over myosin increased 24% (P<0.05) compared to rC0C2 WT control, indicating a causal relationship between variant and decreased MYBPC3 binding to myosin. Human iPSC-derived D389V het cardiomyocytes display an increase in lipid peroxide and reactive oxygen species by +3- and +7-fold P<0.01, respectively, compared to noncarrier controls. Conclusion: D389V decreases interaction between MYBPC3 and myosin S2, causing reduced cardiac function and providing mechanistic evidence that it contributes to the etiology of HCM.

scholarly journals An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction

2005 ◽  
Vol 203 (1) ◽  
pp. 53-61 ◽  
Author(s):  
Andreas D. Niederbichler ◽  
Laszlo M. Hoesel ◽  
Margaret V. Westfall ◽  
Hongwei Gao ◽  
Kyros R. Ipaktchi ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cecal Ligation ◽  
Left Ventricular ◽  
C5a Receptor ◽  
Blocking Antibody ◽  
Cardiomyocyte Contractility ◽  
Complement C5a ◽  
The Complement System

Defective cardiac function during sepsis has been referred to as “cardiomyopathy of sepsis.” It is known that sepsis leads to intensive activation of the complement system. In the current study, cardiac function and cardiomyocyte contractility have been evaluated in rats after cecal ligation and puncture (CLP). Significant reductions in left ventricular pressures occurred in vivo and in cardiomyocyte contractility in vitro. These defects were prevented in CLP rats given blocking antibody to C5a. Both mRNA and protein for the C5a receptor (C5aR) were constitutively expressed on cardiomyocytes; both increased as a function of time after CLP. In vitro addition of recombinant rat C5a induced dramatic contractile dysfunction in both sham and CLP cardiomyocytes, but to a consistently greater degree in cells from CLP animals. These data suggest that CLP induces C5aR on cardiomyocytes and that in vivo generation of C5a causes C5a–C5aR interaction, causing dysfunction of cardiomyocytes, resulting in compromise of cardiac performance.

Multipotent Adult Progenitor Cells (MAPCs) Improve Cardiac Function after Ischemic Injury.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1701-1701
Author(s):  
Jakub Tolar ◽  
Xiahong Wang ◽  
Scott Bell ◽  
Yasuhiro Nakamura ◽  
Ron T. McElmurry ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Fluorescent Protein ◽  
Sleeping Beauty ◽  
Left Ventricular ◽  
Whole Body ◽  
Myocardial Repair ◽  
Surgical Suture ◽  
Injured Myocardium

Abstract MAPCs are pluripotent cells derived from mesenchymal stromal cells (MSCs) in adult bone marrow. In contrast to MSCs, MAPCs differentiate into various lineages of mesodermal, ectodermal and endodermal origin, and contribute to numerous terminally differentiated tissues in the recipients. This capacity is enhanced in the setting of injury, suggesting a possible role of MAPCs in repair and regeneration in disease states. We aimed to investigate the capacity of MAPCs to aid in myocardial repair in hearts with postinfarction remodeling. We reasoned that as MAPCs differentiate to both endothelium and cardiomyocytes in vitro and as engraftment of delivered cells depends on establishing adequate blood flow in the ischemic region, MAPCs may represent the optimal cell type to contribute to both angiogenesis and the parenchymal tissue to regenerate function of injured myocardium. To study engraftment and survival of MAPCs, we labeled adult murine C57BL/6 MAPCs with firefly luciferase and DsRed2 fluorescent protein using non-viral Sleeping Beauty transposons, and injected them into myocardium of C57BL/6 adult mice with acute myocardial infarction (AMI). Mice were anesthetized, intubated and mechanically ventilated using a small-animal respirator. Under a stereomicroscope the heart was accessed via left thoracotomy. The left anterior descending coronary artery was ligated at mid-level between apex and base with a 9-0 surgical suture to produce AMI. Twenty minutes later, intramyocardial injections of labeled MAPCs in saline, or saline alone were administered at five distinct injection sites at boarder zone of AMI (total MAPC dose = 106/mouse). Chest was closed in layers and animals were allowed to recover. Mice were followed with echocardiography and in vivo whole body bioluminescent imaging. Seventy days after AMI, MAPCs recipients (N=6) had significantly less severe left ventricular (LV) dilatation evidenced by a smaller LV end-diastolic and LV end-systolic dimensions when compared to control mice infused with saline (N=4) (average±standard deviation, 4.7±0.2 mm versus 5.3±0.5 mm, p=0.05; and 3.7±0.2 mm versus 4.4±0.6 mm, p=0.03, respectively). In addition, ejection and shortening fractions were significantly higher in MAPC recipients (36±2% versus 30±3%, p=0.004; and 20±1% versus 16±2%, p=0.004, respectively). Luciferase signals emitted from donor MAPCs were easily detectable in MAPC recipients 100 days after MAPC infusion, at which point the animals were harvested. Analyses are ongoing to determine whether MAPCs and their progeny contributed to expansion of coronary vasculature (capillary density), or formed or modified injured myocardial tissue. Alternatively, both populations of repair cells could have been derived from donor (DsRed2+) MAPCs, or donor MAPCs could have provided permissive local environment to recruit recipient cells and enhance endogeneous regeneration. In summary, these findings provide evidence that MAPCs persist long term in injured myocardium and document the potential of MAPCs for improvement of cardiac function after ischemic myocardial injury. Jakub Tolar and Xiaohong Wang contributed equally to this study.

scholarly journals 3496 Mesenchymal Stem Cell Extracellular Vesicle Delivery in a Shear-Thinning Hydrogel For Therapy in an Acute Myocardial Infarction Model: A Comparative Analysis

2019 ◽  
Vol 3 (s1) ◽  
pp. 109-109
Author(s):  
Drew Goldberg ◽  
Ann Gaffey ◽  
Minna Chen ◽  
Elizabeth Li ◽  
Samuel Kim ◽  
...  
Keyword(s):  
Therapeutic Effect ◽  
Shear Thinning ◽  
Left Ventricular ◽  
Border Zone ◽  
Angiogenic Potential ◽  
Angiogenesis Assay ◽  
Rat Hearts ◽  
Hemodynamic Assessment

OBJECTIVES/SPECIFIC AIMS: The primary aim is to assess differences in therapeutic effect between MSC and EPC EVs on acute ischemic rat hearts through delivery in a biocompatible and shear-thinning hydrogel. Primary outcomes for therapeutic assessment include an in-vitro angiogenesis assay and in-vivo hemodynamic analysis, mainly identifying differences in ejection fraction and contractility. Secondary hemodynamic outcomes include cardiac output, stroke volume, and end-diastolic pressure volume relationship (EDPVR). Secondary structural outcomes include post-mortem scar analysis and immunohistochemistry (IHC) staining for angiomyogenesis. METHODS/STUDY POPULATION: MSCs and EPCs will be cultured according to previously published protocols. EVs will be isolated from cultured cell lines through precipitation methods with polyethylene glycol. EVs will be qualitatively analyzed with nanoparticle tracking analysis (NTA) and flow cytometry. The shear thinning hydrogel (STG) will be constructed using a hyaluronic backbone conjugated to adamantane or beta-cyclodextrin, ultimately facilitating guest-host interactions with shear thinning properties. Controls and treatment groups mixed with the hydrogel will be injected into the border zone of infarcted Wistar rat hearts immediately following a left anterior descending artery ligation. Hemodynamic assessment will be performed at four weeks through left ventricular catheter based pressure-volume recordings. Ex-vivo analysis will include scar thickness assessment using Masson collagen staining and IHC stain for vessel (anti-vonWillebrand factor; anti-Isolectin) and myocyte formation (anti-cardiac Troponin I). RESULTS/ANTICIPATED RESULTS: We hypothesize that, in-vitro, MSC-EVs will demonstrate non-inferior angiogenic potential as compared to EPC-EVs. We posit that MSC-EVs will demonstrate superior therapeutic effect to EPC-EVs in-vivo as measured by functional hemodynamics and structural assessment. We have successfully isolated MSC and EPC EVs and have validated uniformity across EV populations (Figure 1). Preliminary data from the angiogenesis assay (n=3) demonstrated that MSC-EV and EPC-EV produce non-significantly different angiogenic potential as measured by number of vascular meshing extremes (p=0.144) and length of master vascular segment (p=0.193), with significant differences compared to either positive or negative controls. DISCUSSION/SIGNIFICANCE OF IMPACT: Novel regenerative therapies are needed for patients with a history of AMI given current limitations to therapy and sequelae of ischemic heart disease. Delivery of extracellular vesicles through a shear-thinning gel is a novel “off-the-shelf” translational approach to address the current clinical need.

Expression of SERCA isoform with faster Ca2+ transport properties improves postischemic cardiac function and Ca2+ handling and decreases myocardial infarction

2007 ◽  
Vol 293 (4) ◽  
pp. H2418-H2428 ◽  
Author(s):  
M. A. Hassan Talukder ◽  
Anuradha Kalyanasundaram ◽  
Xue Zhao ◽  
Li Zuo ◽  
Poornima Bhupathy ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Myocardial Salvage ◽  
Myocardial Infarct Size ◽  
Intracellular Ca ◽  
Developed Pressure

Myocardial ischemia-reperfusion (I/R) injury is associated with contractile dysfunction, arrhythmias, and myocyte death. Intracellular Ca2+ overload with reduced activity of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) is a critical mechanism of this injury. Although upregulation of SERCA function is well documented to improve postischemic cardiac function, there are conflicting reports where pharmacological inhibition of SERCA improved postischemic function. SERCA2a is the primary cardiac isoform regulating intracellular Ca2+ homeostasis; however, SERCA1a has been shown to substitute SERCA2a with faster Ca2+ transport kinetics. Therefore, to further address this issue and to evaluate whether SERCA1a expression could improve postischemic cardiac function and myocardial salvage, in vitro and in vivo myocardial I/R studies were performed on SERCA1a transgenic (SERCA1a+/+) and nontransgenic (NTG) mice. Langendorff-perfused hearts were subjected to 30 min of global ischemia followed by reperfusion. Baseline preischemic coronary flow and left ventricular developed pressure were significantly greater in SERCA1a+/+ mice compared with NTG mice. Independent of reperfusion-induced oxidative stress, SERCA1a+/+ hearts demonstrated greatly improved postischemic (45 min) contractile recovery with less persistent arrhythmias compared with NTG hearts. Morphometry showed better-preserved myocardial structure with less infarction, and electron microscopy demonstrated better-preserved myofibrillar and mitochondrial ultrastructure in SERCA1a+/+ hearts. Importantly, intraischemic Ca2+ levels were significantly lower in SERCA1a+/+ hearts. The cardioprotective effect of SERCA1a was also observed during in vivo regional I/R with reduced myocardial infarct size after 24 h of reperfusion. Thus SERCA1a+/+ hearts were markedly protected against I/R injury, suggesting that expression of SERCA 1a isoform reduces postischemic Ca2+ overload and thus provides potent myocardial protection.

Mechanosensitive release of parathyroid hormone-related peptide from coronary endothelial cells

2002 ◽  
Vol 283 (4) ◽  
pp. H1489-H1496 ◽  
Author(s):  
Heike Degenhardt ◽  
Johanna Jansen ◽  
Rainer Schulz ◽  
Daniel Sedding ◽  
Ruediger Braun-Dullaeus ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Release Rate ◽  
Coronary Flow ◽  
Cyclic Strain ◽  
Rat Hearts ◽  
Perfused Rat Hearts ◽  
Parathyroid Hormone Related Peptide ◽  
Coronary Endothelial Cells

10.1152/ajpheart.00925. 2001.—Parathyroid hormone-related peptide (PTHrP) is expressed throughout the cardiovascular system and is able to dilate vessels. This study investigated whether mechanical forces generated by changes in regional perfusion influence PTHrP release from the coronary vascular bed. Experiments were performed in vitro on saline-perfused rat hearts or isolated coronary endothelial cells exposed to cyclic strain and in vivo in anesthetized pigs. In vitro, PTHrP release from saline-perfused rat hearts was strongly correlated with coronary flow ( r = 0.84). Increasing coronary flow from 5 to 10 ml/min increased PTHrP release from 442 ± 42 to 1,563 ± 167 pg/min. Increasing the viscosity of the perfusate did not change basal PTHrP release. Increasing flow without a concomitant increase in pressure did not lead to an increase in release rate, but reduction in pressure under flow-constant conditions reduced PTHrP release rate. Cyclic strain induced a strain-dependent release of PTHrP from endothelial cells that was inhibited by the addition of a calcium-chelating agent. In vivo, there was a net release of PTHrP in the coronary circulation and decreases in coronary flow and pressure decreased the PTHrP release rate. Bradykinin in the presence of constant pressure increased PTHrP release, probably by increasing the intracellular calcium concentration in coronary endothelial cells. In summary, mechanical forces evoked by blood flow can trigger a constant PTHrP release.

Abstract 107: MicroRNA-31: A Novel Therapeutic Target for Ischemic Heart Disease

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Eliana C Martinez ◽  
Shera Lilyanna ◽  
Leah A Vardy ◽  
Arunmozhiarasi Armugam ◽  
Kandiah Jeyaseelan ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Target Genes ◽  
Subcutaneous Administration ◽  
Left Ventricular ◽  
Ischemic Heart ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Repressive Effect

MicroRNAs (miRNA), small sequences of non-coding RNA which interact with complementary sequences on the 3’untranslated region of target messenger RNAs to modulate translation, have a pivotal role in the development of the heart and its response to injury. Myocardial infarction (MI) triggers a dynamic miRNA response with the potential of yielding therapeutic targets. Following miRNA array profiling in rat hearts 2, 7 and 14 days after MI induced by coronary ligation, we identified a progressive time-dependent up-regulation of miR-31 compared to sham rats. Increase of miR-31 in heart tissue in the acute and subacute phases after MI (up to 90-fold) was also detected by Real-Time PCR (P=0.02 at day 2; P<0.0001 at days 7 and 14, vs. sham). We found that miR-31 has a repressive effect on tissue mRNA expression of cardiac troponin-T (TNNT2), E2F transcription factor 6 (E2F6) and mineralocorticoid receptor (NR3C2). Reporter gene assays showed that miR-31 targets the 3′UTR of these genes, with a marked repressive effect on TNNT2. In vitro, exposure to hypoxia significantly induced the expression of miR-31 in neonatal rat cardiomyocytes (nRCM), rat cardiac fibroblasts (nRCF) and cardiomyoblasts (H9C2) and suppressed the expression of TNNT2, E2F6 and NR3C2 in nRCM and H9C2 cells, and of E2F6 and NR3C2 in nRCF. LNA-based oligonucleotide inhibition of miR-31(miR-31i) in vitro reversed its repressive effect on translation from target genes. Therapeutic modulation of miR-31 expression in vivo after MI via subcutaneous administration of miR-31i (25mg/Kg/q2w) in rats, led to cardiac repression of miR-31 and subsequent enhanced expression of target genes. Also, miR-31i led to preservation of cardiac function and structure by day 14 after treatment. An absolute 10% improvement in left ventricular (LV) ejection fraction (EF) was observed in miR-31i-treated rats from day 2 to 16 after MI, while control rats that received scrambled LNA inhibitor or placebo displayed 23% deterioration in EF (n=6-8/group, P<0.0001). We conclude that miR-31 induction after MI is deleterious to cardiac function and plays an important role in adverse remodeling, while its therapeutic inhibition in vivo ameliorates cardiac dysfunction and prevents the development of post-ischemic heart failure.

scholarly journals Long-term obesity promotes alterations in diastolic function induced by reduction of phospholamban phosphorylation at serine-16 without affecting calcium handling

2014 ◽  
Vol 117 (6) ◽  
pp. 669-678 ◽  
Author(s):  
Ana Paula Lima-Leopoldo ◽  
André S. Leopoldo ◽  
Danielle C. T. da Silva ◽  
André F. do Nascimento ◽  
Dijon H. S. de Campos ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Diastolic Function ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Standard Diet ◽  
Shortening Velocity

Few studies have evaluated the relationship between the duration of obesity, cardiac function, and the proteins involved in myocardial calcium (Ca2+) handling. We hypothesized that long-term obesity promotes cardiac dysfunction due to a reduction of expression and/or phosphorylation of myocardial Ca2+-handling proteins. Thirty-day-old male Wistar rats were distributed into two groups ( n = 10 each): control (C; standard diet) and obese (Ob; high-fat diet) for 30 wk. Morphological and histological analyses were assessed. Left ventricular cardiac function was assessed in vivo by echocardiographic evaluation and in vitro by papillary muscle. Cardiac protein expression of sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2a), calsequestrin, L-type Ca2+ channel, and phospholamban (PLB), as well as PLB serine-16 phosphorylation (pPLB Ser16) and PLB threonine-17 phosphorylation (pPLB Thr17) were determined by Western blot. The adiposity index was higher (82%) in Ob rats than in C rats. Obesity promoted cardiac hypertrophy without alterations in interstitial collagen levels. Ob rats had increased endocardial and midwall fractional shortening, posterior wall shortening velocity, and A-wave compared with C rats. Cardiac index, early-to-late diastolic mitral inflow ratio, and isovolumetric relaxation time were lower in Ob than in C. The Ob muscles developed similar baseline data and myocardial responsiveness to increased extracellular Ca2+. Obesity caused a reduction in cardiac pPLB Ser16 and the pPLB Ser16/PLB ratio in Ob rats. Long-term obesity promotes alterations in diastolic function, most likely due to the reduction of pPLB Ser16, but does not impair the myocardial Ca2+ entry and recapture to SR.

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