Mouse Model Of Acute Myocardial Infarction Research Articles

Nebulized delivery of the MAPKAP kinase 2 peptide inhibitor MMI‐0100 protects against ischemia‐induced systolic dysfunction

Acute myocardial infarction (AMI) results in systolic dysfunction, myocarditis and fibrotic remodeling, which causes irreversible pathological remodeling of the heart. Associated cell death and inflammation cause cytokine release, which activates the p38 MAPK signaling pathway to propagate damaging signals via MAPKAP kinase 2 (MK2). Previously we showed that intraperitoneal injection of a cell permeable peptide inhibitor of MK2, MMI‐0100, protects against fibrosis, apoptosis and systolic dysfunction in a mouse model of AMI, left‐anterior descending coronary artery (LAD) ligation. Here we tested a new route of administration of MMI‐0100: inhalation of nebulized peptide. When given within 30 minutes of AMI and daily for 2 weeks thereafter, both inhaled and injected MMI‐0100 improved cardiac function as measured by conscious echocardiography. Limited fibrosis was observed after two weeks by Massons trichrome staining, suggesting that MMI‐0100 protects the heart prior to the formation of significant fibrosis. These results support a nebulized route of administration of MMI‐0100 can protect the myocardium from ischemic damage.Support or Funding InformationThis work was supported by the National Institutes of Health (R01HL104129 to M.W.), a Fellowship from the Jefferson‐Pilot Corporation (to M.W.), and the Leducq Foundation (to M.W.).

Reciprocal Changes of Circulating Long Non-Coding RNAs ZFAS1 and CDR1AS Predict Acute Myocardial Infarction.

This study sought to evaluate the potential of circulating long non-coding RNAs (lncRNAs) as biomarkers for acute myocardial infarction (AMI). We measured the circulating levels of 15 individual lncRNAs, known to be relevant to cardiovascular disease, using the whole blood samples collected from 103 AMI patients, 149 non-AMI subjects, and 95 healthy volunteers. We found that only two of them, Zinc finger antisense 1 (ZFAS1) and Cdr1 antisense (CDR1AS), showed significant differential expression between AMI patients and control subjects. Circulating level of ZFAS1 was significantly lower in AMI (0.74 ± 0.07) than in non-AMI subjects (1.0 ± 0.05, P < 0.0001), whereas CDR1AS showed the opposite changes with its blood level markedly higher in AMI (2.18 ± 0.24) than in non-AMI subjects (1.0 ± 0.05, P < 0.0001). When comparison was made between AMI and non-AMI, the area under ROC curve was 0.664 for ZFAS1 alone or 0.671 for CDR1AS alone, and 0.691 for ZFAS1 and CDR1AS combination. Univariate and multivariate analyses identified these two lncRNAs as independent predictors for AMI. Similar changes of circulating ZFAS1 and CDR1AS were consistently observed in an AMI mouse model. Reciprocal changes of circulating ZFAS1 and CDR1AS independently predict AMI and may be considered novel biomarkers of AMI.

Nebulized Delivery of the MAPKAP Kinase 2 Peptide Inhibitor MMI-0100 Protects Against Ischemia-Induced Systolic Dysfunction.

Acute myocardial infarction (AMI) results in systolic dysfunction, myocarditis and fibrotic remodeling, which causes irreversible pathological remodeling of the heart. Associated cell death and inflammation cause cytokine release, which activates the p38 MAPK signaling pathway to propagate damaging signals via MAPKAP kinase 2 (MK2). Previously we showed that intraperitoneal injection of a cell permeable peptide inhibitor of MK2, MMI-0100, protects against fibrosis, apoptosis and systolic dysfunction in a mouse model of AMI induced by left-anterior descending coronary artery (LAD) ligation. Here we tested a new route of administration of MMI-0100: inhalation of nebulized peptide. When given within 30 min of AMI and daily for 2 weeks thereafter, both inhaled and injected MMI-0100 improved cardiac function as measured by conscious echocardiography. Limited fibrosis was observed after 2 weeks by Massons trichrome staining, suggesting that MMI-0100 protects the heart prior to the formation of significant fibrosis. These results support a nebulized route of administration of MMI-0100 can protect the myocardium from ischemic damage.

0374 : Cardioprotection against ischemia-reperfusion injury by heart rate control

Acute myocardial infarction (AMI) is a major cause of mortality worldwide. Early reperfusion is the only treatment recommended to reduce infarct size. However, reperfusion induces also deleterious secondary effects called ischemia-reperfusion (IR) injury due to irreversible apoptotic death of cardiomyocytes. Most ischemic episodes are triggered by an increase in heart rate that induces an imbalance between myocardial oxygen delivery and consumption. The BEAUTIFUL clinical trial has demonstrated that moderate heart rate reduction diminishes the frequency of AMI episodes in patients with stable coronary artery disease having increased heart rate at rest. The HCN-mediated I f current and the Ca v 1.3- mediated L-type Ca 2+ currents play important roles in the generation of automaticity and heart rate, therefore they are interesting targets for selective control of heart rate and cardioprotection during AMI. The aim of this study was to investigate if Ca v 1.3 channels could be a putative target to reduce infarct size. Anesthetized C57BL/6J, Ca v 1.3 -/- and Girk4 -/- mice were subjected to a surgical protocol of myocardial IR (40min ischemia-60 min reperfusion). Heart rate was measured with a one-lead surface ECG recording, and infarct size with triphenyl tetrazolium chloride staining. Selective heart rate decrease (26%) in an in vivo mouse model of AMI is associated with reduced IR injury. Ivabradine administration before ischemia significantly reduced infarct size (–33%). Ca v 1.3 -/- mice presented reduced infarct size (–30%) compared to WT mice. In addition, Girk4 -/- mice, a genetic model of moderate tachycardia (10%) displayed increased infarct size (+30%) compared to control mice. These results show a direct relationship between heart rate and IR injury. Heart rate reduction by inhibition of Ca v 1.3 channels constitutes a promising strategy to reduce infarct size.

MicroRNA-150 protects the heart from injury by inhibiting monocyte accumulation in a mouse model of acute myocardial infarction.

MicroRNAs (miRs) and inflammatory monocytes participate in many cardiac pathophysiological processes including acute myocardial infarction (AMI). Recently, we observed that miR-150 is downregulated in injured mouse plasma after AMI as well as in human infarcted monocytes. However, the precise functional role of miR-150 in response to AMI remains unknown. In a mouse model of AMI and in human subjects with AMI, we found that miR-150 expression was reduced in monocytes. In vitro studies showed that ectopic expression of miR-150 markedly reduced monocyte migration and proinflammatory cytokine production, whereas blockade of miR-150 had opposing effects. In vivo studies showed that overexpression of miR-150 in mice resulted in improved cardiac function, reduced myocardial infarction size, inhibition of apoptosis, and reduced inflammatory Ly-6C(high) monocyte invasion levels after AMI. Wild-type mice transplanted with miR-150 null (-/-) bone marrow cells could reverse this protective effect. Mechanistic studies demonstrated that miR-150 inhibited the expression of chemokine receptor 4 (CXCR4), thereby promoting monocyte migration. Our findings indicate that miR-150 acts as a critical regulator of monocyte cell migration and production of proinflammatory cytokines, leading to cardioprotective effects against AMI-induced injury. Thus, miR-150 may be a suitable target for therapeutic intervention in the setting of ischemic heart disease.

Leptin signaling is required for augmented therapeutic properties of mesenchymal stem cells conferred by hypoxia preconditioning.

Hypoxia preconditioning enhances the therapeutic effect of mesenchymal stem cells (MSCs). However, the mechanism underlying hypoxia-induced augmentation of the protective effect of MSCs on myocardial infarction (MI) is poorly understood. We show that hypoxia-enhanced survival, mobility, and protection of cocultured cardiomyocytes were paralleled by increased expression of leptin and cell surface receptor CXCR4. The enhanced activities were abolished by either knockdown of leptin with a selective shRNA or by genetic deficiency of leptin or its receptor in MSCs derived, respectively, from ob/ob or db/db mice. To characterize the role of leptin in the regulation of MSC functions by hypoxia and its possible contribution to enhanced therapeutic efficacy, cell therapy using MSCs derived from wild-type, ob/ob, or db/db mice was implemented in mouse models of acute MI. Augmented protection by hypoxia pretreatment was only seen with MSCs from wild-type mice. Parameters that were differentially affected by hypoxia pretreatment included MSC engraftment, c-Kit(+) cell recruitment to the infarct, vascular density, infarct size, and long-term contractile function. These data show that leptin signaling is an early and essential step for the enhanced survival, chemotaxis, and therapeutic properties of MSCs conferred by preculture under hypoxia. Leptin may play a physiological role in priming MSCs resident in the bone marrow endosteum for optimal response to systemic signaling molecules and subsequent tissue repair.

0324: Cardioprotection against ischemia-reperfusion injury by heart rate control

Myocardial infarction (MI) is the major cause of cardiovascular mortality in western countries. Early reperfusion is the only treatment recommended to reduce infarct size (IS), a crucial prognostic factor of morbidity and mortality. However, reperfusion presents also deleterious effects such as ischemia-reperfusion (IR) injury due to irreversible apoptotic death of cardiomyocytes. Heart rate (HR) is also a determinant of cardiac pathology. Most ischemic episodes are triggered by an increase in HR that induces an imbalance between myocardial oxygen delivery and consumption. The BEAUTIFUL clinical trial (Fox et al . the Lancet, 2008) has demonstrated that moderate HR reduction diminishes the frequency of episodes MI in patients with stable coronary artery disease and increased HR at rest. The HCN-mediated I f current and the Cav1.3-mediated L-type Ca 2+ currents play important roles in the generation of automaticity and HR, therefore they are interesting targets for selective control of HR and cardioprotection (reduced IS) during acute MI. The aim of our study was to investigate if targeting Cav1.3 channels could be an efficient strategy to reduce IS. Cav1.3 -/- mice was used as a genetic model of Cav1.3 inhibition because of the lack of selective blocker. Ivabradine (Iva), the selective f-channel blocker, was used for pure HR reduction as a positive control. Results show that selective HR decrease (40%) in an in vivo mouse model of acute MI is associated with reduced IR injury. Ivabradine administration 30 minutes before ischemia significantly reduced IS (35%). Cav1.3 -/- mice presented reduced IS compared to WT mice (30%). In addition, preliminary results show that Girk4 -/- mice, a genetic model of moderate sinus node tachycardia (10%) displayed increased IS compared to control mice (45%). Taken together these results suggest a direct relationship between HR and IR injury and that inhibition of Cav1.3 channels constitutes a promising strategy to reduce both HR and IS. Abstract 0324 – Figure: Infarct size/area at risk and baseline heart rate

Human Cardiosphere-Derived Cells From Advanced Heart Failure Patients Exhibit Augmented Functional Potency in Myocardial Repair

This study sought to compare the regenerative potency of cells derived from healthy and diseased human hearts. Results from pre-clinical studies and the CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial support the notion that cardiosphere-derived cells (CDCs) from normal and recently infarcted hearts are capable of regenerating healthy heart tissue after myocardial infarction (MI). It is unknown whether CDCs derived from advanced heart failure (HF) patients retain the same regenerative potency. In a mouse model of acute MI, we compared the regenerative potential and functional benefits of CDCs derived from 3 groups: 1) non-failing (NF) donor: healthy donor hearts post-transplantation; 2) MI: patients who had an MI 9 to 35 days before biopsy; and 3) HF: advanced cardiomyopathy tissue explanted at cardiac transplantation. Cell growth and phenotype were identical in all 3 groups. Injection of HF CDCs led to the greatest therapeutic benefit in mice, with the highest left ventricular ejection fraction, thickest infarct wall, most viable tissue, and least scar 3 weeks after treatment. In vitro assays revealed that HF CDCs secreted higher levels of stromal cell-derived factor (SDF)-1, which may contribute to the cells' augmented resistance to oxidative stress, enhanced angiogenesis, and improved myocyte survival. Histological analysis indicated that HF CDCs engrafted better, recruited more endogenous stem cells, and induced greater angiogenesis and cardiomyocyte cell-cycle re-entry. CDC-secreted SDF-1 levels correlated with decreases in scar mass over time in CADUCEUS patients treated with autologous CDCs. CDCs from advanced HF patients exhibit augmented potency in ameliorating ventricular dysfunction post-MI, possibly through SDF-1–mediated mechanisms.

Interleukin‐1β blockade improves cardiac remodelling after myocardial infarction without interrupting the inflammasome in the mouse

The formation of the cryopyrin inflammasome in the heart induces an intense inflammatory response during acute myocardial infarction (AMI), which mediates further damage and promotes adverse cardiac remodelling. Active interleukin-1β (IL-1β) is a key product of the inflammasome, being cleaved by active caspase-1. The aim of this study was to dissect the role of IL-1β from that of the inflammasome by using a neutralizing monoclonal antibody directed against IL-1β and measuring the intensity of the inflammatory response, the activity of caspase-1 in the inflammasome, cardiomyocyte apoptosis and cardiac remodelling in a mouse model of non-reperfused AMI. A mouse monoclonal IgG2a antibody directed against IL-1β (IL-1β-AB; 10 mg kg(-1)) was given i.p. immediately after surgery and repeated 1 week later. Cardiac tissue was analysed at 72 h after surgery in a subgroup of mice for inflammasome aggregates and caspase-1 activity (inflammasome) and for DNA fragmentation and caspase-3 activity (apoptosis). All sham-operated mice were alive at 10 weeks, whereas 40% of the control-antibody-treated mice and 30% of the IL-1β-AB-treated mice died during the 4 weeks after surgery. When compared with vehicle, treatment with the IL-1β-AB did not affect inflammasome formation or caspase-1 activation in the heart tissue at 72 h after AMI nor circulating plasma IL-6 levels, but did inhibit cardiomyocyte apoptosis, limit left ventricular enlargement by 40% (P < 0.01) and improve systolic dysfunction by 17% (P < 0.01) after AMI. These findings suggest that IL-1β mediates the deleterious effects on the heart during the sterile inflammatory response.

24 Initial Results of Simultaneous PET/MRI Evaluation of the Infarcted Mouse Heart

BackgroundChronic heart failure (CHF), as a result of acute myocardial infarction (AMI), is currently a leading cause of death worldwide. The direct assessment of novel treatments targeting CHF in vivo...

Abstract 42: In Vivo Differentiation of Epigenetically Reprogrammed Human Endothelial Progenitor Cells into Cardiomyocytes Enhances Functional and Anatomical Postinfarct Myocardial Repair

Currently, bone marrow derived endothelial progenitor cells (human CD34+ cells, EPC) are being used clinically to improve vascularization in patients with ischemic heart disease. While it is generally accepted that CD34+ cells predominantly work through a paracrine mechanism, there exists no convincing evidence that these cells trans-differentiate into functional cardiomyocytes (CMC). Since ischemic heart disease leads to substantial loss of CMC, improving cardiomyogenic plasticity of an existing autologous cell therapy is of obvious import. EPC and CMC both differentiate from a common mesodermal progenitor however; during EC-specific lineage differentiation, CMC specific genes are epigenetically silenced. We hypothesized that reprogramming of CD34+ cells using small molecules targeting key epigenetic repressive marks may recapitulate their cardiomyogenic potential. Human CD34+ EPCs were treated with inhibitors of histone deacetylases (valproic acid) for 24 hours followed by an additional 24 hours with the DNA methyltransferase inhibitor (5-Azacytidine). This forty-eight hour treatment led to the reactivation of pluripotency associated and CMC specific mRNA expression while EC specific gene expression was maintained. Intra-myocardial transplantation of a sub-therapeutic dose of reprogrammed CD34+ cells in an acute myocardial infarction mouse model showed significant improvement in LV function compared to the same number of control CD34+ cells that are therapeutically equivalent to no treatment at all. This was histologically supported by de novo CMC differentiation. In addition to increased cardiomyogenic plasticity, drug treatment also enhanced the inherent therapeutic capacity of the CD34+ cells as shown by reduced fibrosis, increased capillary density, increased proliferation, increased cell survival and increased secretion of angiogenic factors. Taken together, our results suggest that epigenetically reprogrammed CD34+ cells are “super-CD34+ cells” that have an enhanced paracrine effect, display a more plastic phenotype and improve post-infarct cardiac repair by both neo-cardiomyogenesis and neovascularization.

Enhanced Angiogenic and Cardiomyocyte Differentiation Capacity of Epigenetically Reprogrammed Mouse and Human Endothelial Progenitor Cells Augments Their Efficacy for Ischemic Myocardial Repair

Although bone marrow endothelial progenitor cell (EPC)-based therapies improve the symptoms in patients with ischemic heart disease, their limited plasticity and decreased function in patients with existing heart disease limit the full benefit of EPC therapy for cardiac regenerative medicine. We hypothesized that reprogramming mouse or human EPCs, or both, using small molecules targeting key epigenetic repressive marks would lead to a global increase in active gene transcription, induce their cardiomyogenic potential, and enhance their inherent angiogenic potential. Mouse Lin-Sca1(+)CD31(+) EPCs and human CD34(+) cells were treated with inhibitors of DNA methyltransferases (5-Azacytidine), histone deacetylases (valproic acid), and G9a histone dimethyltransferase. A 48-hour treatment led to global increase in active transcriptome, including the reactivation of pluripotency-associated and cardiomyocyte-specific mRNA expression, whereas endothelial cell-specific genes were significantly upregulated. When cultured under appropriate differentiation conditions, reprogrammed EPCs showed efficient differentiation into cardiomyocytes. Treatment with epigenetic-modifying agents show marked increase in histone acetylation on cardiomyocyte and pluripotent cell-specific gene promoters. Intramyocardial transplantation of reprogrammed mouse and human EPCs in an acute myocardial infarction mouse model showed significant improvement in ventricular functions, which was histologically supported by their de novo cardiomyocyte differentiation and increased capillary density and reduced fibrosis. Importantly, cell transplantation was safe and did not form teratomas. Taken together, our results suggest that epigenetically reprogrammed EPCs display a safe, more plastic phenotype and improve postinfarct cardiac repair by both neocardiomyogenesis and neovascularization.

The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse.

Acute myocardial infarction (AMI) initiates an intense inflammatory response that promotes cardiac dysfunction, cell death, and ventricular remodeling. The molecular events underlying this inflammatory response, however, are incompletely understood. In experimental models of sterile inflammation, ATP released from dying cells triggers, through activation of the purinergic P2X7 receptor, the formation of the inflammasome, a multiprotein complex necessary for caspase-1 activation and amplification of the inflammatory response. Here we describe the presence of the inflammasome in the heart in an experimental mouse model of AMI as evidenced by increased caspase-1 activity and cytoplasmic aggregates of the three components of the inflammasome--apoptosis speck-like protein containing a caspase-recruitment domain (ASC), cryopyrin, and caspase-1, localized to the granulation tissue and cardiomyocytes bordering the infarct. Cultured adult murine cardiomyocytes also showed the inducible formation of the inflammasome associated with increased cell death. P2X7 and cryopyrin inhibition (using silencing RNA or a pharmacologic inhibitor) prevented the formation of the inflammasome and limited infarct size and cardiac enlargement after AMI. The formation of the inflammasome in the mouse heart during AMI causes additional loss of functional myocardium, leading to heart failure. Modulation of the inflammasome may therefore represent a unique therapeutic strategy to limit cell death and prevent heart failure after AMI.

G-CSF and Erythropoietin Combination Therapy for Infarct Repair: Two Plus Two Equals Two?

G-CSF and Erythropoietin Combination Therapy for Infarct Repair: Two Plus Two Equals Two?

Interleukin‐1β modulation using a genetically engineered antibody prevents adverse cardiac remodelling following acute myocardial infarction in the mouse

Division of Cardiology/VCU Pauley Heart Center, Virginia Commonwealth University, 1200 East Broad Street West Hospital, 10th Floor, East Wing, Room 1041, PO Box 980281, Richmond, VA 23298-0281, USA; Victoria Johnson Center, Virginia Commonwealth University, Richmond, VA, USA; School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA; and School of Medicine, University of Colorado, Aurora, CO, USA

Treatment With Recombinant Placental Growth Factor (PlGF) Enhances Both Angiogenesis and Arteriogenesis and Improves Survival After Myocardial Infarction

Placental growth factor (PlGF), a homolog of vascular endothelial growth factor, is reported to stimulate angiogenesis and arteriogenesis in pathological conditions. It was recently demonstrated that PlGF is rapidly produced in myocardial tissue during acute myocardial infarction (MI). However, the effects of exogenous PlGF administration on the healing process after MI are not fully understood. The purpose of the present study was to examine whether PlGF treatment has therapeutic potential in MI. Recombinant human PlGF (rhPlGF: 10 microg) was administered continuously for 3 days in a mouse model of acute MI. rhPlGF treatment significantly improved survival rate after MI and preserved cardiac function relative to control mice. The numbers of CD31-positive cells and alpha-smooth muscle actin-positive vessels in the infarct area were significantly increased in the rhPlGF group. Endothelial progenitor cells (Flk-1(+)Sca-1(+) cells) were mobilized by rhPlGF into the peripheral circulation. Furthermore, rhPlGF promoted the recruitment of GFP-labeled bone marrow cells to the infarct area, but only a few of those migrating cells differentiated into endothelial cells. Exogenous PlGF plays an important role in healing processes by improving cardiac function and stimulating angiogenesis following MI. It can be considered as a new therapeutic molecule.

Anakinra in Experimental Acute Myocardial Infarction—Does Dosage or Duration of Treatment Matter?

Interleukin-1 (IL-1) receptor antagonist (Ra) is a naturally occurring IL-1 blocker with a cardioprotective effect during acute myocardial infarction (AMI). Anakinra, recombinant-human IL-1Ra, has been used to prevent heart failure in a mouse model of AMI. The aim of this study was to determine the optimal therapeutic regimen for anakinra in AMI. We performed dose-response experiments comparing anakinra 1 mg/kg with 100 mg/kg doses, and duration-response experiments comparing 1-week to 2-week treatment. Echocardiography was used to assess cardiac remodeling and systolic function. Histopathology was used to detect apoptotic cardiomyocytes. A higher dose of anakinra was not associated with additional improvement in cardiac remodeling or function. The 2-week anakinra treatment had sustained and more favorable remodeling and systolic function compared to 1-week treatment with significantly smaller left ventricular end-systolic diameter and greater fractional shortening 4 weeks after AMI. Anakinra inhibits apoptosis and ameliorates cardiac remodeling up to 4 weeks after infarction. A 2-week regimen is superior to a 1-week regimen, whereas a higher dose did not provide any further benefit over standard doses.

CCL3 (MIP-1α) levels are elevated during acute coronary syndromes and show strong prognostic power for future ischemic events

As chemokines are considered instrumental in thrombotic plaque rupture and erosion as well as in ischemia-reperfusion injury processes, we aimed to identify previously unknown chemokines associated with acute coronary syndromes. Plasma of 44 patients with acute myocardial infarction (AMI) and 22 controls were profiled for a panel of chemokines by multiplex analysis. Levels of CCL3 were prospectively verified in 54 patients with unstable angina pectoris (UAP). An AMI mouse model was used to assess the relationship between differentially expressed chemokines and myocardial ischemia. CCL3 levels were significantly elevated in AMI vs. controls (P=0.02) albeit, that adjustment for confounding factors attenuated this association. In support of a direct association with cardiac ischemia CCL3 levels were also seen to be elevated in patients with UAP at baseline and significantly down-regulated after 180 days (P<0.001). Importantly, baseline upper quartile levels were strongly correlated with future acute coronary syndromes (Likelihood Ratio 11.5; P<0.01). Furthermore circulating levels of CCL3 were significantly enhanced after AMI in mice (P=0.02), while CCR5+ T-cell numbers were increased as well, suggestive of CCL3 driven T-cell homing towards the ischemic area. CCL3 levels are elevated during ACS and released upon ischemia. Since CCL3 specifically predicts future cardiovascular events, it may serve as a predictive biomarker.

Elevated plasma level of placental growth factor is correlated with peripheral monocyte fraction in patients with acute myocardial infarction

Bone mallow derived stem cells (BMSM) participate in wound healing and regeneration of infarct tissue in acute myocardial infarction (AMI). However, it remains unknown how infarct heart tissue stimulates and recruits BMSC to the injured heart. Placental growth factor (PlGF) stimulates angiogenesis through binding to VEGF receptor-1, and induces BMSC peripheral mobilization. Accordingly, we studied plasma PlGF levels and white blood cell profile after AMI in human, and also studied the heart tissue expression of PlGF of AMI mouse model. Method and Results: 35 patients AMI were enrolled. The plasma PlGF levels of AMI patients significantly increased compared with controls (36.8 + /−31.9, 13.3 + /−5.2 pg/ml, p < 0.0001). Monocyte fraction was elevated in peripheral blood from 3rd to 7th day of AMI, and PlGF positively correlated to peak monocyte fraction (r = 0.496, p < 0.005). Plasma levels of VEGF elevated in AMI, but did not correlate to monocyte fraction. In AMI mouse, PlGF mRNA expression was significantly (26.6 folds, p < 0.001) increased in infarct heart compared with sham operated heart. Furthermore, immunohistochemical staining showed that PlGF protein was overexpressed mainly in vascular tissue in infarct region, but scarcely in non-infarct region. Vascular expression of PlGF protein was not detected in sham-operated heart. Conclusion: Elevated plasma PlGF might have effect on the recruitment of monocyte, as well as vascular progenitor cells, from bone marrow to peripheral circulation.

1042-84 Elevated plasma level of placental growth factor is correlated with peripheral monocyte fraction in patients with acute myocardial infarction

Bone mallow derived stem cells (BMSM) participate in wound healing and regeneration of infarct tissue in acute myocardial infarction (AMI). However, it remains unknown how infarct heart tissue stimulates and recruits BMSC to the injured heart. Placental growth factor (PlGF) stimulates angiogenesis through binding to VEGF receptor-1, and induces BMSC peripheral mobilization. Accordingly, we studied plasma PlGF levels and white blood cell profile after AMI in human, and also studied the heart tissue expression of PlGF of AMI mouse model. Method and Results: 35 patients AMI were enrolled. The plasma PlGF levels of AMI patients significantly increased compared with controls (36.8 + /−31.9, 13.3 + /−5.2 pg/ml, p < 0.0001). Monocyte fraction was elevated in peripheral blood from 3rd to 7th day of AMI, and PlGF positively correlated to peak monocyte fraction (r = 0.496, p < 0.005). Plasma levels of VEGF elevated in AMI, but did not correlate to monocyte fraction. In AMI mouse, PlGF mRNA expression was significantly (26.6 folds, p < 0.001) increased in infarct heart compared with sham operated heart. Furthermore, immunohistochemical staining showed that PlGF protein was overexpressed mainly in vascular tissue in infarct region, but scarcely in non-infarct region. Vascular expression of PlGF protein was not detected in sham-operated heart. Conclusion: Elevated plasma PlGF might have effect on the recruitment of monocyte, as well as vascular progenitor cells, from bone marrow to peripheral circulation.