Parathyroid hormone-related peptide improves contractile function of stunned myocardium in rats and pigs

2003 ◽  
Vol 284 (1) ◽  
pp. H49-H55 ◽  
Author(s):  
Johanna Jansen ◽  
Petra Gres ◽  
Christian Umschlag ◽  
Frank R. Heinzel ◽  
Heike Degenhardt ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Myocardial Function ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Stunned Myocardium ◽  
Coronary Resistance ◽  
Regional Myocardial Function ◽  
Related Peptide

The effect of synthetic parathyroid hormone (PTH)-related peptide [PTHrP(1–34)] on regional myocardial function was studied in 11 anesthetized pigs. Intracoronary infusion of PTHrP (cumulative dose: 14 ± 1 μg) decreased coronary resistance to 33 ± 2% of baseline ( P < 0.05) and regional myocardial function to 90 ± 3% of baseline (not significant). Ischemia-reperfusion alters the activity of several kinases and therefore possibly the myocardial effects of PTHrP. In stunned myocardium, induced by 20-min ischemia and 30-min reperfusion, the dose of PTHrP reducing coronary resistance to a minimum of 29 ± 2% was decreased to 8 ± 2 μg ( P < 0.05). Regional myocardial function was no longer decreased but increased to 132 ± 9% ( P < 0.05). The increase in regional myocardial function during PTHrP was inversely related to baseline function at 30-min reperfusion in vivo ( r = 0.9) as well as in myocytes isolated from stunned pig hearts ( r = 0.7). In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, blockade of endogenous PTHrP byd-Trp12-Tyr34-PTH(7–34) attenuated the recovery of left ventricular developed pressure by 30 ± 14% ( P < 0.05). Thus endogenous and exogenous PTHrP impact on the function of stunned myocardium.

Parathyroid hormone-related peptide improves myocardial contractile function of stunned myocardium in vivo

2001 ◽  
Vol 33 (6) ◽  
pp. A52
Author(s):  
Johanna Janson ◽  
Petra Gires ◽  
Christian Umschlag ◽  
Heike Degenhardt ◽  
Klaus-Dieter Schluetee ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Contractile Function ◽  
Stunned Myocardium ◽  
Related Peptide ◽  
Myocardial Contractile ◽  
Parathyroid Hormone Related Peptide

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.

Sex differences in the myocardial inflammatory response to ischemia-reperfusion injury

2005 ◽  
Vol 288 (2) ◽  
pp. E321-E326 ◽  
Author(s):  
Meijing Wang ◽  
Lauren Baker ◽  
Ben M. Tsai ◽  
Kirstan K. Meldrum ◽  
Daniel R. Meldrum
Keyword(s):  
Sex Differences ◽  
Inflammatory Response ◽  
P38 Mapk ◽  
Myocardial Function ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Mapk Signaling ◽  
Left Ventricular ◽  
Rt Pcr ◽  
Tnf Α

The myocardium generates inflammatory mediators during ischemia-reperfusion (I/R), and these mediators contribute to cardiac functional depression and apoptosis. The great majority of these data have been derived from male animals and humans. Sex has a profound effect over many inflammatory responses; however, it is unknown whether sex affects the cardiac inflammatory response to acute myocardial I/R. We hypothesized the existence of inherent sex differences in myocardial function, expression of inflammatory cytokines, and activation of the p38 mitogen-activated protein kinase (MAPK) signaling pathway after I/R. Isolated rat hearts from age-matched adult males and females were perfused (Langendorff), and myocardial contractile function was continuously recorded. After I/R, myocardium was assessed for expression of TNF-α, IL-1β, and IL-6 (RT-PCR, ELISA); IL-1α and IL-10 mRNA (RT-PCR); and activation of p38 MAPK (Western blot). All indexes of postischemic myocardial function [left ventricular developed pressure, left ventricular end-diastolic pressure, and maximal positive (+dP/d t) and negative (−dP/d t) values of the first derivative of pressure] were significantly improved in females compared with males. Compared with males, females had decreased myocardial TNF-α, IL-1β, and IL-6 (mRNA, protein) and decreased activation of p38 MAPK pathway. These data demonstrate that hearts from age-matched adult females are relatively protected against I/R injury, possibly due to a diminished inflammatory response.

Free radicals inhibit endothelium-dependent dilation in the coronary resistance bed

1988 ◽  
Vol 255 (4) ◽  
pp. H765-H769 ◽  
Author(s):  
D. J. Stewart ◽  
U. Pohl ◽  
E. Bassenge
Keyword(s):  
Free Radicals ◽  
Perfusion Pressure ◽  
Soluble Guanylate Cyclase ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Progressive Increase ◽  
Coronary Resistance ◽  
Resistance Vessel

Oxygen free radicals contribute significantly to ischemia-reperfusion myocardial damage in vivo. We studied the effect of reactive products of O2 generated by electrolysis of the saline perfusate on coronary vasomotor tone and endothelium-mediated vasodilator responsiveness in 41 isolated rabbit hearts. Under constant flow conditions, electrolysis induced a progressive increase in perfusion pressure associated with a modest reduction in myocardial contractile function. The responses to the endothelium-independent vasodilators papaverine and adenosine tended to be increased by 1.5- to 2-fold, indicating that the increase in perfusion pressure was due, at least in part, to increased resistance vessel tone. However, resistance vessel dilations to the endothelium-dependent agents acetylcholine and serotonin were markedly reduced. Various degrees of protection against increases in perfusion pressure and inhibition of endothelium-dependent dilation during electrolysis were obtained with catalase, a scavenger of hydrogen peroxide; superoxide dismutase, a scavenger of superoxide; and desferrioxamine, which chelates iron and thereby inhibits hydroxyl radical production. Furthermore the action of nitroprusside, a direct-acting stimulator of soluble guanylate cyclase, was not diminished during the electrolytic treatment. We conclude that inhibition of endothelium-dependent dilation is a prominent action of reactive products of O2 in the coronary resistance bed. In combination with a free radical-induced increase in resistance vessel tone this might limit recovery of myocardial perfusion post ischemia.

Abstract 313: STIM1 Silencing Reverses Pressure-overload Induced Cardiac Hypertrophy In Mice

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Ludovic O Bénard ◽  
Daniel S Matasic ◽  
Mathilde Keck ◽  
Anne-Marie Lompré ◽  
Roger J Hajjar ◽  
...  
Keyword(s):  
Ventricular Hypertrophy ◽  
Contractile Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Aortic Banding ◽  
Cross Section Area ◽  
Abdominal Aortic ◽  
Section Area

STromal Interaction Molecule 1 (STIM1), a membrane protein of the sarcoplasmic reticulum, has recently been proposed as a positive regulator of cardiomyocyte growth by promoting Ca2+ entry through the plasma membrane and the activation of Ca2+-mediated signaling pathways. We demonstrated that STIM1 silencing prevented the development of left ventricular hypertrophy (LVH) in rats after abdominal aortic banding. Our aim was to study the role of STIM1 during the transition from LVH to heart failure (HF). For experimental timeline, see figure. Transverse Aortic Constriction (TAC) was performed in C57Bl/6 mice. In vivo gene silencing was performed using recombinant Associated AdenoVirus 9 (AAV9). Mice were injected with saline or with AAV9 expressing shRNA control or against STIM1 (shSTIM1) (dose: 1e+11 viral genome), which decreased STIM1 cardiac expression by 70% compared to control. While cardiac parameters were similar between the TAC groups at weeks 3 and 6, shSTIM1 animals displayed a progressive and total reversion of LVH with LV walls thickness returning to values observed in sham mice at week 8. This reversion was associated with the development of significant LV dilation and severe contractile dysfunction, as assessed by echography. Hemodynamic analysis confirmed the altered contractile function and dilation of shSTIM1 animals. Immunohistochemistry showed a trend to more fibrosis. Despite hypertrophic stimuli, there was a significant reduction in cardiac myocytes cross-section area in shSTIM1-treated animals as compared to other TAC mice. This study showed that STIM1 is essential to maintain compensatory LVH and that its silencing accelerates the transition to HF.

Abstract P293: Endogenous Lats2 Plays an Important Role in Mediating Myocardial Injury Caused by Ischemia/Reperfusion Through Inhibition of FoxO3

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Dan Shao ◽  
Peiyong Zhai ◽  
Junichi Sadoshima
Keyword(s):  
Oxidative Stress ◽  
Myocardial Injury ◽  
Ischemia Reperfusion ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Dominant Negative ◽  
Area At Risk ◽  
Perfused Heart ◽  
Developed Pressure

Lats2 is a tumor suppressor and a serine/threonine kinase, acting downstream of mammalian sterile 20 like kinase1 (Mst1), which stimulates apoptosis and inhibits hypertrophy in cardiomyocytes (CM). We investigated the role of Lats2 in mediating myocardial injury after ischemia/reperfusion (IR). Phosphorylation of YAP, an in vivo substrate of Lats2, was increased after 45 minutes ischemia followed by 24 hours reperfusion in control mouse hearts compared with sham, but not in dominant negative (DN) Lats2 transgenic mouse (Tg) hearts, suggesting that Lats2 is activated by IR. The size of myocardial infarction (MI)/area at risk was significantly smaller in Tg mice than in NTg mice (19% and 49%, p<0.01). And there were fewer TUNEL positive cells in Tg than in NTg mice (0.04% and 0.11%, p<0.05). Following 30 min of global ischemia and 60 min of reperfusion in Langendorff perfused heart preparations, left ventricular (LV) systolic pressure (100 vs 71mmHg, p<0.05) and LV developed pressure (79 vs 47 mmHg, p<0.05) were significantly greater in Tg than in NTg mice, indicating that suppression of Lats2 induces better functional recovery after IR. Oxidative stress, as evaluated by 8-OHdG staining, was attenuated in Tg mice. In cultured CMs, DN-Lats2 significantly decreased H 2 O 2 -induced cell death. Overexpression of Lats2 significantly downregulated (51% and 75%, p<0.05), whereas that of DN-Last2 upregulated (100 and 70%, p<0.05), MnSOD and catalase, suggesting that Lats2 negatively regulates expression of antioxidants. Reporter gene assays showed that overexpression of Lats2 significantly inhibits (−70%), whereas knocking down Lats2 by sh-Lats2 increases (+60%), FoxO3-mediated transcriptional activity. Overexpression of Lats2 in CMs inhibited FoxO3 expression, whereas that of DN-Lats2 significantly inhibited FoxO3 downregulation after IR in vivo, suggesting that Lats2 negatively regulates FoxO3 protein expression, which may lead to the downregulation of MnSOD and catalase. Taken together, these results suggest that endogenous Lats2 plays an important role in mediating myocardial injury in response to IR, In part through downregulation of FoxO3 and consequent downregulation of antioxidants and increased oxidative stress in the heart.

Cooperative interactions between extracellular matrix, integrins and parathyroid hormone-related peptide regulate parietal endoderm differentiation in mouse embryos

Development ◽  
1995 ◽  
Vol 121 (12) ◽  
pp. 4137-4148 ◽  
Author(s):  
O. Behrendtsen ◽  
C.M. Alexander ◽  
Z. Werb
Keyword(s):  
Extracellular Matrix ◽  
Parathyroid Hormone ◽  
Mouse Embryos ◽  
Collagen Type Iv ◽  
Related Peptide ◽  
Parathyroid Hormone Related Peptide ◽  
Parietal Endoderm ◽  
Alpha V Beta 3 ◽  
Endodermal Cells

The outgrowth of parietal endoderm (PE) cells from precursor endodermal cells is one of the first differentiation events that occur in mouse embryos. We have analyzed the molecular determinants of this process by placing isolated inner cell masses (ICMs) on defined extracellular matrix substrata in microdrop cultures. Differentiation and outgrowth of PE required a fibronectin substratum. Laminin supported the adhesion and outgrowth of visceral endoderm (VE) and actively suppressed the differentiation of PE in mixtures of fibronectin and laminin. Collagen type IV, gelatin, vitronectin or entactin supported little or no endodermal outgrowth. Trophectoderm (TE) cells have been implied to be important in PE induction in vivo. We found that recombination of ICMs in culture with TE cells, or with medium conditioned by TE cells, greatly increased the differentiation of PE. TE cells stimulated PE outgrowth on substrata other than fibronectin. One cytokine secreted by trophoblast and endodermal cells, parathyroid hormone-related peptide (PTHrP), was critical for outgrowth on any substratum. A function-perturbing antibody to PTHrP reduced the number of PE cells, whereas the addition of PTHrP increased that number. Furthermore, addition of PTHrP changed the substratum requirements for outgrowth, making laminin, vitronectin and low concentrations of fibronectin permissive for PE outgrowth. Immunostaining with anti-integrin antibodies showed that fully differentiated PE cells outgrowing on fibronectin expressed alpha 5, alpha 6 and alpha v beta 3 integrins. However, analysis of outgrowths in the presence of function-perturbing antibodies to alpha 5, alpha 6 and alpha v beta 3 integrins showed that these integrins directed PE outgrowth only on fibronectin, laminin and vitronectin substrata, respectively. We have shown that there is a cooperative interplay of extracellular matrix, integrins and PTHrP that modulates PE outgrowth.

Improvement by isosorbide dinitrate of exercise-induced regional myocardial dysfunction

1980 ◽  
Vol 239 (3) ◽  
pp. H399-H405
Author(s):  
T. Kumada ◽  
K. P. Gallagher ◽  
M. Miller ◽  
M. McKown ◽  
F. White ◽  
...  
Keyword(s):  
Isosorbide Dinitrate ◽  
Myocardial Function ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Segment Length ◽  
Wall Thickening ◽  
Regional Myocardial Function ◽  
Exercise Induced ◽  
Coronary Obstruction ◽  
Control Exercise

Sonomicrometry was used in 10 conscious dogs to measure regional segment length and dynamic wall thickness by telemetry in a zone supplied by the left circumflex coronary artery after implantation of an ameroid constrictor. When coronary obstruction was nearly complete and collaterals had developed (24-42 days), control exercise and exercise runs after oral isosorbide dinitrate were carried out. During control runs, significant increases occurred in hemodynamic parameters, and percent shortening in normal segments increased (P < 0.01). During the repeat runs after isosorbide dinitrate, there were smaller increases in left ventricular systolic and end-diastolic pressures and significantly reduced end-diastolic dimensions. In addition, percent wall thickening and percent segment shortening in the ischemic zone did not deteriorate significantly during exercise. In this animal model, which appears to mimic chronic single-vessel coronary heart disease, isosorbide dinitrate can prevent exercise-induced deterioration of regional myocardial function.

Sign in / Sign up

Export Citation Format

Share Document