Abstract 350: Early Cell-Cell Coupling Contributes to Loss of Transplanted Stem Cell Retention and Efficacy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Santipongse Chatchavalvanich ◽  
David L Geenen
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cardiac Function ◽  
Bystander Effect ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Cell Coupling ◽  
Loop Analysis

Bone marrow-derived mesenchymal stem cell (BM-MSC) replacement therapy is beneficial to the heart following ischemia but a significant loss of these cells within hours of administration could diminish their effect. We hypothesized that early coupling between BM-MSC and ischemic cardiomyocytes through gap junctions (GJ) may play a detrimental role in stem cell survival and retention in the acute phase of cell therapy. We seeded HL-1 cardiomyocytes in either normoxic (Nx) or ischemic (Isc) conditions for four hours. Subsequently, BM-MSC were seeded on the HL-1 monolayer and the co-cultures were returned to incubation either in their previous conditions (Nx, Isc) or switched from Isc to Nx condition (ischemia-reperfusion; Isc/Rep) for an additional two hours. Co-cultures were labeled with Annexin V, Sytox Red, and Sca-1 (BM-MSC), and subjected to flow cytometry. Ischemia induced a greater proportion of dead BM-MSC over the two-hour co-culture compared to the Nx group. Isc/Rep resulted in significantly higher early apoptotic but fewer dead BM-MSC. The presence of the GJ inhibitor carbenoxolone (CBX; 100 µM) in the co-culture reduced the number of dead and apoptotic cells in Isc and Isc/Rep groups by 3-5 fold (p<0.05). To determine the effect of GJ inhibition in vivo, we induced ischemia in mice by 90-minute LAD ligation followed by reperfusion for 24 hours. BM-MSC, CBX-treated BM-MSC, or CBX alone were injected at the end of the 90 min Isc period. Twenty-four hours after cell injection, left ventricular diastolic and systolic function was assessed by pressure-volume loop analysis. Isc/Rep caused impaired cardiac function which was attenuated by BM-MSC injection. CBX-treated BM-MSC further enhanced the cardiac function (MSC vs. MSC+CBX: Ees 7.3 ± 1.66 vs. 15.0 ± 5.81; Emax 18.8 ± 6.50 vs. 27.5 ± 9.33; PRSW 49.5 ± 9.89 vs. 99.4 ± 17.4; mean ± SD; p≤0.05; n = 6) while CBX alone did not. While long term integration of stem cells within the myocardium relies on functional GJ, early GJ communication may represent a novel paradigm whereby ischemic cardiomyocytes cause a “bystander effect” in newly transplanted stem cells and thus impair retention and functional benefits.

Load-sensitive measures may overestimate global systolic function in the presence of left ventricular hypertrophy: a comparison with load-insensitive measures

2006 ◽  
Vol 290 (4) ◽  
pp. H1699-H1705 ◽  
Author(s):  
K. A. Connelly ◽  
D. L. Prior ◽  
D. J. Kelly ◽  
M. P. Feneley ◽  
H. Krum ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Systolic Function ◽  
Normal Function ◽  
Left Ventricular ◽  
Doppler Imaging ◽  
Stroke Work ◽  
Sprague Dawley ◽  
Loop Analysis ◽  
Shortening Velocity

Transgenic animal models have provided a vital insight into the pathogenesis of cardiovascular disease, but functional cardiac assessment is often limited by high heart rates and small heart size. We hypothesized that in the presence of concentric left ventricular (LV) hypertrophy (LVH), load-sensitive measures of contractility may be misinterpreted as overestimating global cardiac function, because the normal function of excess sarcomeres may displace a greater volume of blood during contraction. Conductance catheter technology was used to evaluate pressure-volume (P-V) relationships as a load-insensitive method of assessing cardiac function in vivo in 18-wk-old heterozygous (mRen-2)27 transgenic rats (a model of LVH), compared with age-matched Sprague-Dawley (SD) controls. Anesthetized animals underwent echocardiography followed by P-V loop analysis. Blood pressure, body weight, and heart rate were higher in the Ren-2 rats ( P < 0.05). Load-sensitive measures of systolic function, including fractional area change, fractional shortening, ejection fraction, and positive peak rate of LV pressure development, were greater in the Ren-2 than control animals ( P < 0.05). Load-insensitive measures of systolic function, including the preload recruitable stroke work relationship and the end-systolic P-V relationship, were not different between Ren-2 and SD rats. Regional wall motion assessed by circumferential shortening velocity suggested enhanced circumferential fiber contractility in the Ren-2 rats ( P = 0.02), but tissue Doppler imaging, used to assess longitudinal function, was not different between groups. Although conventional measures suggested enhanced systolic function in the Ren-2 rat, load-insensitive measures of contractility were not different between Ren-2 and SD animals. These findings suggest that the normal range of values for load-sensitive indexes of contractility needs to be altered according to the degree of LVH. To accurately identify changes in systolic function, we suggest that a combination of echocardiography with assessment of load-insensitive measures be used routinely.

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 5572: Endothelial-Selective Deletion of Neuregulin-1 Leads to Impaired Tolerance of Ischemic Injury

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Qunhua Huang ◽  
April Kalinowski ◽  
Kashif Jafri ◽  
Monica Palmeri ◽  
Raymond R Russell ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Glucose Uptake ◽  
Cardiac Myocyte ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Ischemic Injury ◽  
Left Ventricular ◽  
Neuregulin 1 ◽  
Compound C

The neuregulin-1 (NRG)/erbB signaling axis is emerging as an important mediator of endothelial/myocyte crosstalk. We have previously shown that NRG can protect cardiac myocytes from apoptosis induced by hypoxic injury and that endothelial cells can provide this NRG in an ex vivo co-culture model. To extend this observation to an intact animal system, we have generated mice with inducible and endothelial-selective deletion of NRG. We hypothesized that animals with decreased endothelial NRG expression would be more susceptible to ischemic injury. Mice carrying a transgene for tamoxifen-inducible expression of cre recombinase under control of the Tie2 promoter were crossed with those carrying homozygously floxed NRG-1 genes. Serial echocardiographic measurements of cardiac function were performed before, during and after tamoxifen induction. There was no significant decrease in cardiac function following the completion of the induction (NRG knockout) protocol. Hearts from these mice underwent a global ischemia/reperfusion protocol in the Langendorff mode. Both resting and post-ischemic +/−dP/dT and left ventricular developed pressure were impaired in the animals with endothelial selective NRG deletion compared to non-induced transgenics or tamoxifen-induced controls. Hearts from the NRG deleted animals released more CPK and contained significantly more apoptotic nuclei compared to controls after ischemia/reperfusion, supporting the idea that endothelial-derived NRG can protect myocytes against apoptosis in vivo. Another mechanism by which loss of NRG may contribute to cardiac dysfunction in the setting of ischemia is by altering cardiac myocyte glucose uptake. We have shown that adult rat cardiomyocyte glucose uptake is significantly increased in response to NRG and that this response is abrogated partially by wortmannin, but completely by wortmannin plus compound C (an inhibitor of AMP-activated protein kinase), suggesting that both AKT and AMPK dependent pathways of glucose uptake may be activated by NRG in adult myocytes. Thus, we conclude that NRG plays an important role in preservation of cardiac myocyte function in vivo and that this may occur as a result of both protection against apoptosis and enhanced glucose metabolism.

Abstract 242: Subcutaneous and Visceral Adipose-Derived Stem Cells Have Similar Biological Properties and Both Improve Cardiac Function of Infarcted Rat Hearts

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Chao Chi ◽  
Bo Xiang ◽  
Jixian Deng ◽  
Fei Wang ◽  
Kanmani Natarajan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cardiac Function ◽  
Formation Rate ◽  
Biological Properties ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Control Group ◽  
Ventricular Ejection Fraction ◽  
Visceral Adipose

Background: Adipose stem cells (ASC) from subcutaneous and visceral adipose tissues have been studied individually. However, it is unclear whether ASC from the two sources have different biological properties and, more importantly, whether one sub-type of ASC is more effective in treatment of CHF. This study was designed to address these concerns. Methods: Morphology, yield, proliferation, surface markers, and cytokine secretion of rat subcutaneous ASC (S-ASC) and visceral ASC (V-ASC) were analyzed. A rat model of myocardial infarction (MI) was established by occlusion of the LAD. 7 days after MI, S-ASC (n = 11), V-ASC (n = 11), and cell culture medium (Control, n = 7) were injected into the infarct rim, respectively. Cardiac function of the infarcted hearts was monitored with MRI for 6 months. Results: Both S-ASC and V-ASC exhibited a fibroblast-like morphology and expressed stromal cell markers (CD29, CD90 and CD105). No significant expression of hematopoietic markers (CD11b, CD34 and CD45) was found. Under appropriate conditions, both cells could differentiate to adipocyte- and osteocyte-like cells. Both of them expressed a significant level of HGF, IGF-1 and VEGF. As to their differences, V-ASC had approximately 3-times greater cell yield and a lower colony-formation rate (9.8±1.0% vs.13.5±2.6%) relative to S-ASC. In contrast, S-ASC showed a significantly greater growth rate (Doubling Time: 17.9 h vs. 26.0 h) relative to V-ASC. Both S-ASC and V-ASC-treated hearts showed a significantly greater left ventricular ejection fraction (LVEF, 58.3% and 56.7%) than the control group (LVEF, 47.2%) at end of 6 months. LVEF between the two ASC-treated groups was not significantly different. Finally, the implanted stem cells were readily detected in vivo with MRI for at least 6 months. Myocardial tissue sections showed existence of ASC and their locations matched with MRI signals. Conclusions: S-ASC and V-ASC share several biological characteristics. Both provide comparable significant improvement on cardiac function. Moreover, these implanted cells can be reliably tracked for at least 6 months using MRI. We conclude that the S-ASC and V-ASC are equally effective for treatment of heart failure.

Abstract 14878: Exosomes From Induced Pluripotent Stem Cell-Derived Cardiomyocytes vs Mesenchymal Stem Cells Demonstrate Differential Restoration of Myocardial Function in a Porcine Ischemia Reperfusion Injury Model

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Connor G OBrien ◽  
Evgeniya Vaskova ◽  
Yuko Tada ◽  
Jihye Jung ◽  
Gentaro Ikeda ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Ischemia Reperfusion ◽  
Induced Pluripotent Stem Cell ◽  
Left Ventricular ◽  
Myocardial Scar ◽  
Injury Model ◽  
Induced Pluripotent

Introduction: Coronary artery disease is a leading cause of death worldwide. Ischemic injury leads to myocardial dysfunction, resulting in heart failure. Exosomes have emerged as a promising therapeutic for restoring the failing heart. Fundamental questions such as cell of origin and molecular cargo for optimal therapeutic effect are areas of intense research. Our lab has shown that the exosomes from bone marrow derived mesenchymal stem cells (MSC-Ex) and induced pluripotent stem cell derived cardiomyocytes (iCM-Ex) both restore injured murine myocardium. These results led us to compare the therapeutic effects of MSC-Ex vs. iCM-Ex in a porcine myocardial ischemia reperfusion (IR) injury model, a step toward predicting efficacy in humans. Hypothesis: iCM-Ex is superior to MSC-Ex in restoring the injured porcine myocardium. Methods and Results: Pigs underwent ischemia reperfusion (IR) injury, consisting of 1 hour percutaneous balloon occlusion of the proximal left anterior descending artery immediately distal to the first septal artery. Following IR injury, 5 x 10 11 exosomes were delivered in ten, 500μL intramyocardial injections using a BioCardio Helix™ catheter. Biplane ventriculography was used to target the peri-infarct region. At 2- and 4-weeks post-infarct, pigs underwent cardiac MRI (cMRI) with ciné, delayed-enhanced (DEMRI) and manganese-enhanced (MEMRI) MRI. Pigs treated with iCM-Ex (n = 5) demonstrated a 41% improvement in left ventricular ejection fraction (LVEF, p = 0.004) and 35% reduction in indexed left ventricular end diastolic volume (p = 0.008) compared to controls while MSC-Ex (N = 5) did not demonstrate significant functional improvement. Furthermore, DEMRI and MEMRI showed a 21% reduction in myocardial scar (p = 0.14) in iCM-Ex treated animals compared to control while MSC-Ex group showed no difference. RNA-seq of the exosomes and transcriptomic analysis of the ex vivo myocardium will delineate the molecular mechanism of action and the putative intracellular pathway. Conclusion: iCM-Ex is superior to MSC-Ex in improving LVEF and reducing myocardial scar formation following ischemic insult. Comparative analysis between iCM-Ex and MSC-Ex is underway to identify the molecular targets that restore the failing heart.

Abstract 16200: Chronic Central Nervous System Actions of Leptin Protect Against Myocardial Ischemia/reperfusion Injury

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Ana Carolina Mieko Omoto ◽  
Jussara M do Carmo ◽  
Elizabeth R Flynn ◽  
Sydney P Moak ◽  
Xuan Li ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cardiac Function ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Histological Evaluation ◽  
Acid Oxidation ◽  
Collagen Deposition

While myocardial reperfusion is the most effective therapy to reduce mortality after myocardial infarction, it can paradoxically exacerbate ischemic injury. We recently showed that leptin, via its actions on the central nervous system (CNS), improved left ventricular function in a model of heart failure induced by permanent ligation of the left anterior coronary artery (LAD). To investigate whether leptin also protects the heart against ischemia/reperfusion (I/R) injury via its actions in the CNS, we instrumented female Wistar rats (15 weeks of age) with an intracerebroventricular (ICV) cannula into the lateral ventricle, and after 7 days of recovery and baseline assessment of cardiac function by echocardiography (VisualSonics VEVO-3100®), myocardial I/R was induced by temporary LAD ligation (60 min). Vehicle (saline, 0.5 μL/hr, n=6) or leptin (15 μg/day, n=7) were infused ICV for 28 consecutive days starting 20 min after reperfusion using osmotic minipump connected to the ICV cannula. Echocardiographic assessment of cardiac function was performed every week and at the end of the 4 th week of treatment, the heart was collected and processed for protein analysis and histological evaluation of infarct size and collagen deposition. Compared to vehicle treatment, chronic ICV leptin infusion significantly reduced infarcted area (21±2 vs. 37±4 %), septal collagen deposition (2.2±0.2 vs. 4.0±0.7 %), and markedly attenuated systolic dysfunction as evidenced by increased ejection fraction 4 weeks post I/R (59±1 vs. 30±2%), stroke volume (296±19 vs. 159±8 μL) and cardiac output (108±5 vs.63±4 μL/min). ICV leptin infusion also prevented the increase in left atrium to aorta diameter ratio (1.5±0.1 vs. 2±0.1 mm), an index of cardiac congestion. In addition, we found a 2-fold increase in the ratio of phospho-acetyl-CoA carboxylase (p-ACC) to total ACC protein expression, a marker of fatty acid oxidation, in hearts of leptin-treated rats compared with vehicle infusion. These results indicate that leptin exerts powerful beneficial CNS-mediated effects on the heart that improve systolic function and protect the myocardium against I/R injury. Our results also suggest that these beneficial actions may involve improved myocardial bioenergetics.

Cardiac function in hearts isolated from a rat model deficient in mast cells

2005 ◽  
Vol 288 (2) ◽  
pp. H632-H637 ◽  
Author(s):  
Richard H. Kennedy ◽  
Martin Hauer-Jensen ◽  
Jacob Joseph
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cardiac Function ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Balloon Catheter ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Adult Rats

Several studies have examined the role of mast cells in the myocardial response to injury such as that caused by hypertension and ischemia-reperfusion. However, little is known about the influence of mast cells on normal myocardial structure and function. The present experiments examined cardiac function in Langendorff-perfused hearts isolated from 6- and 9-mo-old male mast cell-deficient ( Ws/ Ws) and mast cell-competent rats. A fluid-filled balloon catheter was used to measure left ventricular diastolic and systolic function at increasing preload volumes. At 6 mo of age, mast cell-deficient rats showed a slight cardiac hypertrophy (as monitored by heart weight and heart weight-to-body weight ratio) but no significant change in maximum observed systolic or diastolic function. In contrast, at 9 mo of age, the mast cell-deficient group showed no signs of hypertrophy but displayed a diastolic dysfunction characterized by decreased compliance without a significant decline in maximum observed basal −dP/d tmax. There were no significant differences in maximum observed values for measures of systolic function (developed pressure and +dP/d tmax). In summary, the results of this study in adult rats suggest that mast cells influence cardiac function in the absence of injury and that observed differences between mast cell-competent and -deficient animals vary with age. Thus it is important to consider these “physiological” actions and resulting changes in function when studying effects of insult in mast cell-deficient models.

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.

scholarly journals A new model of congestive heart failure in rats

2011 ◽  
Vol 301 (3) ◽  
pp. H994-H1003 ◽  
Author(s):  
Jiqiu Chen ◽  
Elie R. Chemaly ◽  
Li Fan Liang ◽  
Thomas J. LaRocca ◽  
Elisa Yaniz-Galende ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Cardiac Function ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Remote Myocardium ◽  
Male Rats ◽  
Lv Function ◽  
New Model

Current rodent models of ischemia/infarct or pressure-volume overload are not fully representative of human heart failure. We developed a new model of congestive heart failure (CHF) with both ischemic and stress injuries combined with fibrosis in the remote myocardium. Sprague-Dawley male rats were used. Ascending aortic banding (Ab) was performed to induce hypertrophy. Two months post-Ab, ischemia-reperfusion (I/R) injury was induced by ligating the left anterior descending (LAD) artery for 30 min. Permanent LAD ligation served as positive controls. A debanding (DeAb) procedure was performed after Ab or Ab + I/R to restore left ventricular (LV) loading properties. Cardiac function was assessed by echocardiography and in vivo hemodynamic analysis. Myocardial infarction (MI) size and myocardial fibrosis were assessed. LV hypertrophy was observed 4 mo post-Ab; however, systolic function was preserved. LV hypertrophy regressed within 1 mo after DeAb. I/R for 2 mo induced a small to moderate MI with mild impairment of LV function. Permanent LAD ligation for 2 mo induced large MI and significant cardiac dysfunction. Ab for 2 mo followed by I/R for 2 mo (Ab + I/R) resulted in moderate MI with significantly reduced ejection fraction (EF). DeAb post Ab + I/R to reduce afterload could not restore cardiac function. Perivascular fibrosis in remote myocardium after Ab + I/R + DeAb was associated with decreased cardiac function. We conclude that Ab plus I/R injury with aortic DeAb represents a novel model of CHF with increased fibrosis in remote myocardium. This model will allow the investigation of vascular and fibrotic mechanisms in CHF characterized by low EF, dilated LV, moderate infarction, near-normal aortic diameter, and reperfused coronary arteries.

In vivo gene delivery of HSP70i by adenovirus and adeno-associated virus preserves contractile function in mouse heart following ischemia-reperfusion

2006 ◽  
Vol 291 (6) ◽  
pp. H2905-H2910 ◽  
Author(s):  
Darrell D. Belke ◽  
Bernd Gloss ◽  
John M. Hollander ◽  
Eric A. Swanson ◽  
Hervé Duplain ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Viral Vector ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Viral Gene ◽  
Mouse Heart ◽  
Adeno Associated Virus

Inducible heat shock protein 70 (HSP70i) has been shown to exert a protective effect in hearts subjected to ischemia-reperfusion. Although studied in heat-shocked animals and in transgenic mice that constitutively overexpress the protein, the therapeutic application of the protein in the form of a viral vector-mediated HSP70i expression has not been widely examined. Accordingly, we have examined the effects of HSP70i delivered in vivo to the left ventricular free wall of the heart via viral gene therapy in mice. The affect of virally mediated HSP70i expression in preserving cardiac function following ischemia-reperfusion was examined after short-term expression (5-day adenovirus mediated) and long-term expression (8-mo adeno-associated virus mediated) in mice by subjecting ex vivo Langendorff perfused hearts to a regime of ischemia-reperfusion. Both vectors were capable of increasing HSP70i expression in the heart, and neither vector had any effect on cardiac function during aerobic (preischemic) perfusion when compared with corresponding controls. In contrast, both adenovirus-mediated and adeno-associated virus-mediated expression of HSP70i improved the contractile recovery of the heart after 120 min of reperfusion following ischemia. This study demonstrates the feasibility of using both short- and long-term expression of virally mediated HSP70i as a therapeutic intervention against cardiac ischemia-reperfusion injury.

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