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Browsing by Subject "Cardioprotection"
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Item Estradiol-treated mesenchymal stem cells improve myocardial recovery after ischemia(Elsevier, 2009-04) Erwin, Graham S.; Crisostomo, Paul R.; Wang, Yue; Wang, Meijing; Markel, Troy A.; Guzman, Mike; Sando, Ian C.; Sharma, Rahul; Meldrum, Daniel R.; Surgery, School of MedicineBACKGROUND: Stem cell therapy is a promising treatment modality for injured cardiac tissue. A novel mechanism for this cardioprotection may include paracrine actions. Our lab has recently shown that gender differences exist in mesenchymal stem cell (MSC) paracrine function. Estrogen is implicated in the cardioprotection found in females. It remains unknown whether 17beta-estradiol (E2) affects MSC paracrine function and whether E2-treated MSCs may better protect injured cardiac tissue. We hypothesize that E2-exposed MSCs infused into hearts prior to ischemia may demonstrate increased vascular endothelial growth factor (VEGF) production and greater protection of myocardial function compared to untreated MSCs. MATERIALS AND METHODS: Untreated and E2-treated MSCs were isolated, cultured, and plated and supernatants were harvested for VEGF assay (enzyme-linked immunosorbent assay). Adult male Sprague-Dawley rat hearts (n = 13) were isolated and perfused via Langendorff model and subjected to 15 min equilibration, 25 min warm global ischemia, and 40 min reperfusion. Hearts were randomly assigned to perfusate vehicle, untreated male MSC, or E2-treated male MSC. Transcoronary delivery of 1 million MSCs was performed immediately prior to ischemia in experimental hearts. RESULTS: E2-treated MSCs provoked significantly more VEGF production than untreated MSCs (933.2 +/- 64.9 versus 595.8 +/- 10.7 pg/mL). Postischemic recovery of left ventricular developed pressure was significantly greater in hearts infused with E2-treated MSCs (66.9 +/- 3.3%) than untreated MSCs (48.7 +/- 3.7%) and vehicle (28.9 +/- 4.6%) at end reperfusion. There was also greater recovery of the end diastolic pressure with E2-treated MSCs than untreated MSCs and vehicle. CONCLUSIONS: Preischemic infusion of MSCs protects myocardial function and viability. E2-treated MSCs may enhance this paracrine protection, which suggests that ex vivo modification of MSCs may improve therapeutic outcome.Item Glucagon-like peptide-1 (7-36) but not (9-36) augments cardiac output during myocardial ischemia via a Frank-Starling mechanism(Springer, 2014) Goodwill, Adam G.; Tune, Johnathan D.; Noblet, Jillian N.; Conteh, Abass M.; Sassoon, Daniel; Casalini, Eli D.; Mather, Kieren J.; Department of Cellular & Integrative Physiology, IU School of MedicineThis study examined the cardiovascular effects of GLP-1 (7-36) or (9-36) on myocardial oxygen consumption, function and systemic hemodynamics in vivo during normal perfusion and during acute, regional myocardial ischemia. Lean Ossabaw swine received systemic infusions of saline vehicle or GLP-1 (7-36 or 9-36) at 1.5, 3.0, and 10.0 pmol/kg/min in sequence for 30 min at each dose, followed by ligation of the left circumflex artery during continued infusion at 10.0 pmol/kg/min. Systemic GLP-1 (9-36) had no effect on coronary flow, blood pressure, heart rate or indices of cardiac function before or during regional myocardial ischemia. Systemic GLP-1 (7-36) exerted no cardiometabolic or hemodynamic effects prior to ischemia. During ischemia, GLP-1 (7-36) increased cardiac output by approximately 2 L/min relative to vehicle-controls (p = 0.003). This response was not diminished by treatment with the non-depolarizing ganglionic blocker hexamethonium. Left ventricular pressure-volume loops measured during steady-state conditions with graded occlusion of the inferior vena cava to assess load-independent contractility revealed that GLP-1 (7-36) produced marked increases in end-diastolic volume (74 ± 1 to 92 ± 5 ml; p = 0.03) and volume axis intercept (8 ± 2 to 26 ± 8; p = 0.05), without any change in the slope of the end-systolic pressure-volume relationship vs. vehicle during regional ischemia. GLP-1 (9-36) produced no changes in any of these parameters compared to vehicle. These findings indicate that short-term systemic treatment with GLP-1 (7-36) but not GLP-1 (9-36) significantly augments cardiac output during regional myocardial ischemia, via increases in ventricular preload without changes in cardiac inotropy.Item Non-responsiveness to cardioprotection by ischaemic preconditioning in Ossabaw minipigs with genetic predisposition to, but without the phenotype of the metabolic syndrome(Springer, 2022-11-11) Kleinbongard, Petra; Lieder, Helmut Raphael; Skyschally, Andreas; Alloosh, Mouhamad; Gödecke, Axel; Rahmann, Sven; Sturek, Michael; Heusch, Gerd; Anatomy, Cell Biology and Physiology, School of MedicineThe translation of successful preclinical and clinical proof-of-concept studies on cardioprotection to the benefit of patients with reperfused acute myocardial infarction has been difficult so far. This difficulty has been attributed to confounders which patients with myocardial infarction typically have but experimental animals usually not have. The metabolic syndrome is a typical confounder. We hypothesised that there may also be a genuine non-responsiveness to cardioprotection and used Ossabaw minipigs which have the genetic predisposition to develop a diet-induced metabolic syndrome, but before they had developed the diseased phenotype. Using a prospective study design, a reperfused acute myocardial infarction was induced in 62 lean Ossabaw minipigs by 60 min coronary occlusion and 180 min reperfusion. Ischaemic preconditioning by 3 cycles of 5 min coronary occlusion and 10 min reperfusion was used as cardioprotective intervention. Ossabaw minipigs were stratified for their single nucleotide polymorphism as homozygous for valine (V/V) or isoleucine (I/I)) in the γ-subunit of adenosine monophosphate-activated protein kinase. Endpoints were infarct size and area of no-reflow. Infarct size (V/V: 54 ± 8, I/I: 54 ± 13% of area at risk, respectively) was not reduced by ischaemic preconditioning (V/V: 55 ± 11, I/I: 46 ± 11%) nor was the area of no-reflow (V/V: 57 ± 18, I/I: 49 ± 21 vs. V/V: 57 ± 21, I/I: 47 ± 21% of infarct size). Bioinformatic comparison of the Ossabaw genome to that of Sus scrofa and Göttingen minipigs identified differences in clusters of genes encoding mitochondrial and inflammatory proteins, including the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. The phosphorylation of STAT3 at early reperfusion was not increased by ischaemic preconditioning, different from the established STAT3 activation by cardioprotective interventions in other pig strains. Ossabaw pigs have not only the genetic predisposition to develop a metabolic syndrome but also are not amenable to cardioprotection by ischaemic preconditioning.Item Remote ischemic conditioning in Ossabaw minipigs induces the release of humoral cardioprotective triggers, but the myocardium does not respond with reduced infarct size(American Physiological Society, 2022) Lieder, Helmut Raphael; Skyschally, Andreas; Sturek, Michael; Heusch, Gerd; Kleinbongard, Petra; Anatomy, Cell Biology and Physiology, School of MedicineIschemic preconditioning (IPC; brief cycles of coronary occlusion/reperfusion) is operative in all species tested so far and reduces infarct size through the release of trigger molecules and activation of signal transducer and activator of transcription (STAT)3 in pigs. We have recently demonstrated that IPC failed to protect Ossabaw minipigs, which had a genetic predisposition to, but not yet established a metabolic syndrome, from infarction and did not activate STAT3. We now subjected Ossabaw minipigs to remote ischemic conditioning (RIC; 4 × 5 min/5 min bilateral hindlimb ischemia-reperfusion) and analyzed the release of cardioprotective triggers into the circulation with the aim to distinguish whether IPC failed to stimulate trigger release or to activate intracellular signaling cascades upstream of STAT3. RIC or a placebo protocol, respectively, was induced in anesthetized pigs before 60 min/180 min coronary occlusion/reperfusion. Plasma, prepared from Ossabaw minipigs after RIC or placebo, was infused into isolated rat hearts subjected to 30 min/120 min global ischemia-reperfusion. In the Ossabaw minipigs, RIC did not reduce infarct size (49.5 ± 12.1 vs. 56.0 ± 11.8% of area at risk with placebo), and STAT3 was not activated. In isolated rat hearts, infusion of RIC plasma reduced infarct size (19.7 ± 6.7 vs. 33.2 ± 5.5% of ventricular mass with placebo) and activated STAT3. Pretreatment of rat hearts with the STAT3 inhibitor stattic abrogated such infarct size reduction and STAT3 activation. In conclusion, Ossabaw minipigs release cardioprotective triggers in response to RIC into the circulation, and lack of cardioprotection is attributed to myocardial nonresponsiveness. NEW & NOTEWORTHY: Ischemic conditioning reduces myocardial infarct size in all species tested so far. In the present study, we used Ossabaw minipigs that had a genetic predisposition to, but not yet established a metabolic syndrome. In these pigs, remote ischemic conditioning (RIC) induced the release of cardioprotective triggers but did not reduce infarct size. Transfer of their plasma, however, reduced infarct size in isolated recipient rat hearts, along with signal transducer and activator of transcription (STAT)3 activation.