Abstract 342: Cortical Bone Stem Cell Therapy Alters Macrophage Phenotype and Reduces Cardiac Cell Death After Myocardial Infarction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Alexander R Hoachlandr-Hobby ◽  
Remus M Berretta ◽  
Yijun Yang ◽  
Eric Feldsott ◽  
Hajime Kubo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Immune Response ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Cortical Bone ◽  
Myocardial Injury ◽  
Border Zone ◽  
Paracrine Factors ◽  
Infarct Border Zone ◽  
Infarct Border

Acute injuries to the heart, like myocardial infarction (MI), contribute to the development and pathology of heart failure (HF). Reperfusion of the ischemic heart greatly increases survival but results in reperfusion injury that can account for up to 50% of the final infarct size. The inflammatory response to MI-induced myocardial injury is thought to be responsible for the propagation of reperfusion injury into the infarct border zone, expanding myocardial damage. We have previously shown in a swine model of MI that intramyocardial injections of cortical bone-derived stem cells (CBSCs) into the infarct border zone has no acute cardioprotective effect but reduces scar size by half and prevents the decline of ejection fraction and LV dilation 3 months after MI. Our new preliminary data show that CBSCs have potent immunoregulatory capabilities. Therefore, we hypothesize that CBSC treatment has an effect on the immune response to MI that improves the wound healing response to myocardial injury and mitigates LV remodeling and infarct size 3 months later. To test this hypothesis, we characterized the effects of CBSC paracrine factors on macrophages in vitro and found that CBSC-treated macrophages express higher levels of CD206, produce more IL-1RA and IL-10, and phagocytose apoptotic myocytes more efficiently. In addition, macrophages were increased in CBSC-treated swine hearts 7 days after MI compared to controls with a corresponding increase in IL-1RA and TIMP-2. Apoptosis was decreased overall and in macrophages specifically in CBSC-treated animals. From these data we conclude CBSCs may exert an acute pro-reparative effect on the immune response after MI, reducing reperfusion injury and adverse remodeling resulting in improved functional outcomes at later time points.

Abstract 14412: Activation of Autophagic Flux Maintains Mitochondrial Homeostasis During Cardiac Ischemia/reperfusion Injury

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jing Yang ◽  
Geoffrey W CHO ◽  
Lihao He ◽  
Yuxin Chu ◽  
Jin He ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Systolic Function ◽  
Ischemia Reperfusion ◽  
Border Zone ◽  
Autophagic Flux ◽  
Hdac Inhibition ◽  
Infarct Border Zone ◽  
Infarct Border

Background and Hypothesis: Reperfusion injury accounts for ~50% of myocardial infarct size, and clinically efficacious therapies are lacking. Histone deacetylase (HDAC) inhibition enhances cardiomyocyte autophagic activity, mitochondria biogenesis, and blunts ischemia/reperfusion (I/R) injury when given at the time of reperfusion. However, as HDAC inhibition has pleiotropic effects, we will test whether augmentation of autophagic flux using a specific autophagy-inducing peptide, Tat-Beclin (TB), is cardioprotective. Methods: 8-12-week-old, wild-type, C57BL6 mice were randomized into three groups: vehicle control, Tat-Scrambled (TS) peptide, or Tat-Beclin (TB) peptide. Each group was subjected to I/R surgery (45min ischemia, 24h reperfusion). Infarct size, systolic function, and mitochondrial dynamics were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were used to test for cardiomyocyte specificity. Conditional cardiomyocyte ATG7 knockout (ATG7 KO) mice and ATG7 knockdown by siRNA in NRVMs were used to evaluate the role of autophagy. Results: TB treatment at reperfusion reduced infarct size by 20.1±6.3% (n=23, p<0.02) and improved systolic function. Increased autophagic flux and reduced reactive oxygen species (ROS) were observed in the infarct border zone. The cardioprotective effects of TB were abolished in ATG7 KO mice. TB increased mtDNA content in the border zone significantly. In NRVMs subjected to I/R, TB reduced cell death by 41±6% (n=12, p<0.001), decreased ROS, and increased mtDNA content significantly by ~50%. Moreover, TB promoted expression of PGC1α (a major driver of mitochondrial biogenesis) both in the infarct border zone and NRVMs subjected to I/R by ~40%, and increased levels of mitochondrial dynamics gene transcripts Drp1, Fis1, and MFN1 / 2. Conversely, ATG7 knockdown in NRVMs and cardiac ATG7 KO abolished the beneficial effects of TB on mitochondria DNA content. Conclusions: Autophagic flux is an essential process to mitigate myocardial reperfusion injury acting, at least in part, by inducing PGC1α-mediated mitochondrial biogenesis. Augmentation of autophagic flux may emerge as a viable clinical therapy to reduce reperfusion injury in myocardial infarction.

scholarly journals MK5 haplodeficiency decreases collagen deposition and scar size during post-myocardial infarction wound repair

2019 ◽  
Vol 316 (6) ◽  
pp. H1281-H1296 ◽  
Author(s):  
Sherin Ali Nawaito ◽  
Pramod Sahadevan ◽  
Marie-Élaine Clavet-Lanthier ◽  
Philippe Pouliot ◽  
Fatiha Sahmi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Collagen Content ◽  
Post Myocardial Infarction ◽  
Border Zone ◽  
Wild Type ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Infarct Border Zone ◽  
Infarct Border

MK5 is a protein serine/threonine kinase activated by p38, ERK3, and ERK4 MAPKs. MK5 mRNA and immunoreactivity are detected in mouse cardiac fibroblasts, and MK5 haplodeficiency attenuates the increase in collagen 1-α1 mRNA evoked by pressure overload. The present study examined the effect of MK5 haplodeficiency on reparative fibrosis following myocardial infarction (MI). Twelve-week-old MK5+/− and wild-type littermate (MK5+/+) mice underwent ligation of the left anterior descending coronary artery (LADL). Surviving mice were euthanized 8 or 21 days post-MI. Survival rates did not differ significantly between MK5+/+ and MK5+/− mice, with rupture of the LV wall being the primary cause of death. Echocardiographic imaging revealed similar increases in LV end-diastolic diameter, myocardial performance index, and wall motion score index in LADL-MK5+/+ and LADL-MK5+/− mice. Area at risk did not differ between LADL-MK5+/+ and LADL-MK5+/− hearts. In contrast, infarct size, scar area, and scar collagen content were reduced in LADL-MK5+/− hearts. Immunohistochemical analysis of mice experiencing heart rupture revealed increased MMP-9 immunoreactivity in the infarct border zone of LADL-MK5+/− hearts compared with LADL-MK5+/+. Although inflammatory cell infiltration was similar in LADL-MK5+/+ and LADL-MK5+/− hearts, angiogenesis was more pronounced in the infarct border zone of LADL-MK5+/− mice. Characterization of ventricular fibroblasts revealed reduced motility and proliferation in fibroblasts isolated from MK5−/− mice compared with those from both wild-type and haplodeficient mice. siRNA-mediated knockdown of MK5 in fibroblasts from wild-type mice also impaired motility. Hence, reduced MK5 expression alters fibroblast function and scar morphology but not mortality post-MI. NEW & NOTEWORTHY MK5/PRAK is a protein serine/threonine kinase activated by p38 MAPK and/or atypical MAPKs ERK3/4. MK5 haplodeficiency reduced infarct size, scar area, and scar collagen content post-myocardial infarction. Motility and proliferation were reduced in cultured MK5-null cardiac myofibroblasts.

Angiogenesis after acute myocardial infarction

2020 ◽  
Author(s):  
Xuekun Wu ◽  
Marc R Reboll ◽  
Mortimer Korf-Klingebiel ◽  
Kai C Wollert
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Tissue Repair ◽  
Left Ventricular ◽  
Lineage Tracing ◽  
Border Zone ◽  
Angiogenic Response ◽  
Mechanistic Understanding ◽  
Infarct Border Zone ◽  
Infarct Border

Abstract Acute myocardial infarction (MI) inflicts massive injury to the coronary microcirculation leading to vascular disintegration and capillary rarefication in the infarct region. Tissue repair after MI involves a robust angiogenic response that commences in the infarct border zone and extends into the necrotic infarct core. Technological advances in several areas have provided novel mechanistic understanding of postinfarction angiogenesis and how it may be targeted to improve heart function after MI. Cell lineage tracing studies indicate that new capillary structures arise by sprouting angiogenesis from pre-existing endothelial cells (ECs) in the infarct border zone with no meaningful contribution from non-EC sources. Single-cell RNA sequencing shows that ECs in infarcted hearts may be grouped into clusters with distinct gene expression signatures, likely reflecting functionally distinct cell populations. EC-specific multicolour lineage tracing reveals that EC subsets clonally expand after MI. Expanding EC clones may arise from tissue-resident ECs with stem cell characteristics that have been identified in multiple organs including the heart. Tissue repair after MI involves interactions among multiple cell types which occur, to a large extent, through secreted proteins and their cognate receptors. While we are only beginning to understand the full complexity of this intercellular communication, macrophage and fibroblast populations have emerged as major drivers of the angiogenic response after MI. Animal data support the view that the endogenous angiogenic response after MI can be boosted to reduce scarring and adverse left ventricular remodelling. The improved mechanistic understanding of infarct angiogenesis therefore creates multiple therapeutic opportunities. During preclinical development, all proangiogenic strategies should be tested in animal models that replicate both cardiovascular risk factor(s) and the pharmacotherapy typically prescribed to patients with acute MI. Considering that the majority of patients nowadays do well after MI, clinical translation will require careful selection of patients in need of proangiogenic therapies.

scholarly journals A Characterization and Targeting of the Infarct Border Zone in a Swine Model of Myocardial Infarction

2012 ◽  
Vol 5 (5) ◽  
pp. 416-421 ◽  
Author(s):  
Jason M. Duran ◽  
Sharven Taghavi ◽  
Remus M. Berretta ◽  
Catherine A. Makarewich ◽  
Thomas Sharp III ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Border Zone ◽  
Swine Model ◽  
Infarct Border Zone ◽  
Infarct Border

scholarly journals Cardiomyocytes Cellular Phenotypes After Myocardial Infarction

2021 ◽  
Vol 8 ◽  
Author(s):  
Alessandra Maria Lodrini ◽  
Marie-José Goumans
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Contractility ◽  
Border Zone ◽  
Cell Level ◽  
Cellular Processes ◽  
Infarcted Heart ◽  
Ischemic Episode ◽  
Cellular Phenotypes ◽  
Infarct Border Zone ◽  
Infarct Border

Despite the increasing success of interventional coronary reperfusion strategies, mortality related to acute myocardial infarction (MI) is still substantial. MI is defined as sudden death of myocardial tissue caused by an ischemic episode. Ischaemia leads to adverse remodelling in the affected myocardium, inducing metabolic and ionic perturbations at a single cell level, ultimately leading to cell death. The adult mammalian heart has limited regenerative capacity to replace lost cells. Identifying and enhancing physiological cardioprotective processes may be a promising therapy for patients with MI. Studies report an increasing amount of evidence stating the intricacy of the pathophysiology of the infarcted heart. Besides apoptosis, other cellular phenotypes have emerged as key players in the ischemic myocardium, in particular senescence, inflammation, and dedifferentiation. Furthermore, some cardiomyocytes in the infarct border zone uncouple from the surviving myocardium and dedifferentiate, while other cells become senescent in response to injury and start to produce a pro-inflammatory secretome. Enhancing electric coupling between cardiomyocytes in the border zone, eliminating senescent cells with senolytic compounds, and upregulating cardioprotective cellular processes like autophagy, may increase the number of functional cardiomyocytes and therefore enhance cardiac contractility. This review describes the different cellular phenotypes and pathways implicated in injury, remodelling, and regeneration of the myocardium after MI. Moreover, we discuss implications of the complex pathophysiological attributes of the infarcted heart in designing new therapeutic strategies.

Abstract 1096: Cytokine Enhancement with Hgf Or Vegf in the Infarct Border Zone is Key to Attenuating the Negative Remodelling after Myocardial Infarction

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Sonja Schrepfer ◽  
Tobias Deuse ◽  
Christoph Peter ◽  
William Stein ◽  
Tim Doyle ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Treatment Strategies ◽  
Border Zone ◽  
Cytokine Release ◽  
Intramyocardial Injection ◽  
Paracrine Effects ◽  
Infarct Border Zone ◽  
Infarct Border

Adult mesenchymal stem cell (MSC)-based treatment strategies have been proposed to alleviate the consequences of myocardial infarction (MI). The cytokine release of ischemic myocardium was investigated in vivo after LAD ligations in mice and in vitro in cultured cardiomyocytes. Of all cytokines that were at least 5-fold upregulated during ischemia, only HGF and VEGF proved to promote MSC proliferation, and chemotaxis in vitro. Homing of intranenously (IV) injected MSCs (0.5×106 per animal) into the infarct border zone after LAD ligation was inefficient (1±0.5 cells/HPF). Cytokine enhancement (CE) of HGF or VEGF by intramyocardial injection at the time of MI significantly facilitated MSC homing (11±4 cells/HPF and 7±4 cells/HPF, respectively; p=0.001). To our knowledge, this is the first study monitoring cardiac geometry and function over a long-term period of 6 months. using ECG-triggered contrast Micro-CT. It revealed that the progressive decrease in EF over time (to 19±1%) could be attenuated by CE with HGF (29±6%; p=0.003) or VEGF (28±4%; p=0.004) and subsequent IV MSC injection. However, LVEFs of animals treated with CE with HGF or VEGF only, but received no MSC injection, were similar to those groups that also received IV MSCs (p=0.127 and p=0.54, respectively). Best results were finally achieved by prolonged presence of HGF or VEGF, achieved by intramyocardial injection of MSCs stably transfected to produce HGF or VEGF and firefly luciferase into the infarct border zone. Duration of cytokine release was estimated by monitoring MSC survival using in vivo bioluminescence imaging (BLI). BLI signals were detectable for 10 days in contrast to the rapid fate of the cytokines after single dose administration in the CE group, resulting in preserved LVEFs at 6 months This study highlights the beneficial effect of HGF and VEGF to attenuate the negative LV remodelling after MI and diminishes the role of the MSCs to a pure delivery system for paracrine effects.

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