Healing Of Myocardial Infarction Research Articles

Inflammatory Cascade Unveiled: Exploring Complications and Therapeutic Strategies for Post-Myocardial Infarction Inflammation (A Literature Review)

This comprehensive literature review delves into the inflammatory ramifications of myocardial infarction (MI), a global health concern with reported prevalences of 3.8% and 9.5% among those under and over 60 years, respectively. While the inflammatory cascade plays a crucial role in MI healing, its dysregulation can lead to complications. Recent advancements have unveiled intricate cellular and molecular pathways. The common post-MI complication of pericarditis poses diagnostic challenges due to symptom similarities with MI, requiring careful management, particularly in cases of Dressler’s syndrome. Promising therapeutic strategies, including anti-inflammatory approaches and ongoing drug development, are under exploration. Future research directions involve delving into unknown factors, identifying novel therapeutic targets, and validating emerging treatments in larger trials, emphasizing the imperative need for continued investigation into the inflammatory consequences of MI. Keyword: Anti-inflammatory Strategies, Dressler’s Syndrome, Pericarditis, Post-cardiac Injury Syndrome.

Technical challenges in small animal models for mimicking human ischemic cardiovascular diseases

Animal models are essential for exploring pathophysiology and testing novel therapy options of human metabolic cardiovascular diseases. Several small animal models have been developed during the last decades to study effects on myocardial infarct size, healing or cardiac remodeling and thus outcome after ligation of a left coronary artery. The present review describes the value and limitations of small animal models mimicking human ischemic myocardial insult and offers technical tips for using them. A perspective on future improved small animal models mimicking human cardiovascular diseases is also given.

C-C Motif Chemokine 2 Regulates Macrophage Polarization and Contributes to Myocardial Infarction Healing.

Macrophages are crucial immune cells that play essential roles in the healing of myocardial infarction (MI), undergoing continuous polarization throughout this process. C-C motif chemokine 2 (CCL2) is a chemokine that regulates inflammatory responses during MI. However, the extent to which CCL2 influences macrophage polarization and MI healing remains incompletely understood. In this study, we investigate the role of CCL2 in macrophage polarization and MI healing. Our findings reveal that CCL2 is differentially expressed in lipopolysaccharide (LPS)-induced M1 and interleukin (IL)-4-induced M2 RAW264.7 macrophages. Knockdown of CCL2 attenuates TNF-α secretion stimulated by LPS, while overexpression of CCL2 mitigates IL-10 production triggered by IL-4 in these macrophages. Moreover, CCL2 deficiency disrupts LPS-induced M1 polarization, whereas CCL2 overexpression reduces M2 polarization of RAW264.7 macrophages induced by IL-4. Further exploration indicates that the promotion of M1 polarization by CCL2 is significantly impaired by inhibition of the p38-mediated MAPK pathway and NF-κB pathway. In a MI mouse model, CCL2 knockdown remarkably reduces infarct size, collagen synthesis, and the expression of cardiac fibrosis and hypertrophy markers. The activity of the p38-mediated MAPK pathway and NF-κB pathway is downregulated by CCL2 knockdown as well. Additionally, the number of total macrophages and M1 macrophages in the infarct decreases, while the number of M2 macrophages increases upon CCL2 deficiency. In conclusion, these results suggest that CCL2 is a key regulator of macrophage polarization, controlling MI healing in vivo.

Abstract 15024: Immunomodulatory Effects of Human Embryonic Stem Cell-Derived Epicardial Cells in Myocardial Infarct Healing

Background: Acute myocardial infarction (AMI) causes excessive myocardium damage, including epicardium. Cell therapy by implantation of human pluripotent stem cell (hPSC)-derived cardiovascular cells has been tested in the infarcted hearts of preclinical models and clinical studies. However, whether hPSC-derived epicardial cells (hEPs) can be a therapeutic approach for infarcted hearts remains unclear. AMI induces inflammatory cascades, leading to multifaceted processes of myocardial injury and healing, whereas it is unknown whether hEPs regulate immune responses, especially macrophage plasticity at the acute phase of MI. Aims: to determine whether hEP implantation promotes myocardial infarct healing and modulates inflammatory response. Results: intramyocardial injection of hEPs at the acute phase of MI ameliorated functional worsening (p<0.001 vs. MI control) and scar formation of adult male NOD-SCID mouse hearts (p<0.05 vs. MI control) at day 28 post-MI, concomitantly with enhanced cardiomyocyte survival, angiogenesis, and lymphangiogenesis (p<0.05 vs. MI control). Mechanistically, hEPs suppressed AMI-induced increases of type I interferon (IFN-I) response, infiltration and cytokine-release of inflammatory cells, and promoted polarization of reparative macrophages. These effects were blocked by a IFN-I receptor agonist RO8191 in mouse model of MI. Moreover, hEP abundantly secreted intelectin 1 (ITLN1), which interacted with IFN-β and mimicked the effects of hEP-condition medium in the suppression of IFN-β-stimulated responses in macrophages and promotion of reparative macrophage polarization. However, ITLN1 downregulation in the hEPs canceled beneficial effects of hEPs in anti-inflammation and anti-IFN-I response, and in cardiac repair of infarcted hearts. Conclusions: our resutls demonstrate the reparative effects of hEP implantations in the infarcted hearts and reveal hEPs as an inflammatory modulator in promoting infarct healing via paracrine factor-mediated cell-cell communications. These findings provide new knowledges for the functions and mechanisms of hEPs for cardiac repair and suggest a therapeutic option of hEPs for ischemic myocardial repair.

A Core-Shell Nanoreinforced Ion-Conductive Implantable Hydrogel Bioelectronic Patch with High Sensitivity and Bioactivity for Real-Time Synchronous Heart Monitoring and Repairing.

To achieve synchronous repair and real-time monitoring the infarcted myocardium based on an integrated ion-conductive hydrogel patch is challenging yet intriguing. Herein, a novel synthetic strategy is reported based on core-shell-structured curcumin-nanocomposite-reinforced ion-conductive hydrogel for synchronous heart electrophysiological signal monitoring and infarcted heart repair. The nanoreinforcement and multisite cross-linking of bioactive curcumin nanoparticles enable well elasticity with negligible hysteresis, implantability, ultrahigh mechanoelectrical sensitivity (37ms), and reliable sensing capacity (over 3000 cycles) for the nanoreinforced hydrogel. Results of in vitro and in vivo experiments demonstrate that such solely physical microenvironment of electrophysiological and biomechanical characteristics combining with the role of bioactive curcumin exert the synchronous benefit of regulating inflammatory microenvironment, promoting angiogenesis, and reducing myocardial fibrosis for effective myocardial infarction (MI) repair. Especially, the hydrogel sensors offer the access for achieving accurate acquisition of cardiac signals, thus monitoring the whole MI healing process. This novel bioactive and electrophysiological-sensing ion-conductive hydrogel cardiac patch highlights a versatile strategy promising for synchronous integration of in vivo real-time monitoring the MI status and excellent MI repair performance.

Phospholipids, the Masters in the Shadows during Healing after Acute Myocardial Infarction.

Phospholipids are major components of cell membranes with complex structures, high heterogeneity and critical biological functions and have been used since ancient times to treat cardiovascular disease. Their importance and role were shadowed by the difficulty or incomplete available research methodology to study their biological presence and functionality. This review focuses on the current knowledge about the roles of phospholipids in the pathophysiology and therapy of cardiovascular diseases, which have been increasingly recognized. Used in singular formulation or in inclusive combinations with current drugs, phospholipids proved their positive and valuable effects not only in the protection of myocardial tissue, inflammation and fibrosis but also in angiogenesis, coagulation or cardiac regeneration more frequently in animal models as well as in human pathology. Thus, while mainly neglected by the scientific community, phospholipids present negligible side effects and could represent an ideal target for future therapeutic strategies in healing myocardial infarction. Acknowledging and understanding their mechanisms of action could offer a new perspective into novel therapeutic strategies for patients suffering an acute myocardial infarction, reducing the burden and improving the general social and economic outcome.

Coronary perivascular adipose tissue inflammation – An autopsy-based histomorphological study from a tertiary care hospital in South India

Background: The connective tissue around the blood vessels in the body (except cerebral vessels) is called perivascular adipose tissue (PVAT). Whenever there is a vascular pathology, PVAT increases in volume and becomes dysfunctional. This change promotes dedifferentiation of adipocytes. PVAT inflammation (PVATi) starts secreting anti-vasodilation and pro-inflammatory substance, leading to infiltration of inflammatory immune cells, endothelial dysfunction which initiates atherosclerosis followed by stenosis. It is now recognized that PVATi plays an important role in many vascular pathologies. Aims and Objectives: The objectives of the study were (1) to estimate the prevalence of coronary PVATi in an autopsy case, (2) to determine the coronary atherosclerotic changes and cardiac changes associated with PVATi, and (3) to correlate the association of PVATi with age and sex. Materials and Methods: Autopsy-based retrospective study done for a period of 1 year. From the autopsy requisition form, details such as age, gender, cause of death (COD), and gross findings of the organs were noted. The left coronary artery, right coronary artery, left anterior descending artery, left circumflex artery, and myocardium slides were reviewed microscopically to note the presence of PVATi, type of inflammatory infiltrate, atherosclerotic changes, percentage of stenosis, and associated cardiac changes. Range, frequencies, percentage, mean, standard deviation, and P-value were calculated. P<0.05 was taken as statistically significant. Results: Fifty-two cases showed PVATi among 400 autopsy cases performed during the period of 1 year. Forty-two cases were from males and 10 cases were from female. The most common COD noted was sudden death following chest pain. Ten cases showed PVATi involving major branches of the coronary artery. Thirty-six cases showed hypertrophic changes in myocardium. Acute myocardial infarction (MI) and old healed MI were noted in 7 and 23 cases, respectively. Conclusion: PVATi of coronary arteries has significant association with atherosclerosis and sudden death cardiac death.

Gasotransmitter-Induced Therapeutic Angiogenesis: A Biomaterial Prospective.

Gasotransmitters such as NO, H2S, and CO have emerged as key players in the regulation of various pathophysiological functions, prompting the development of gas therapy for various pathogeneses. Deficient production of gasotransmitters has been linked to various diseases such as hypertension, endothelial dysfunction, myocardial infarction, ischemia, and impaired wound healing, as they are involved in the regulatory action of angiogenesis. A better understanding of the regulatory mechanisms has given new hope to address the vascular impairment caused by the breakthroughs in gasotransmitters as therapeutics. However, the unstable nature and poor target specificity of gas donors limit the full efficacy of drugs. In this regard, biomaterials that possess excellent biocompatibility and porosity are ideal drug carriers to deliver the gas transmitters in a tunable manner for therapeutic angiogenesis. This review article provides a comprehensive discussion of biomaterial-based gasotransmitter delivery approaches for therapeutic angiogenesis. The critical role of gasotransmitters in modulating angiogenesis during tissue repair as well as their challenges and future directions are demonstrated.

Blockade of Wnt Secretion Attenuates Myocardial Ischemia-Reperfusion Injury by Modulating the Inflammatory Response.

Wnt (a portmanteau of Wingless and Int-1) signaling in the adult heart is largely quiescent. However, there is accumulating evidence that it gets reactivated during the healing process after myocardial infarction (MI). We here tested the therapeutic potential of the Wnt secretion inhibitor LGK-974 on MI healing. Ischemia/reperfusion (I/R) injury was induced in mice and Wnt signaling was inhibited by oral administration of the porcupine inhibitor LGK-974. The transcriptome was analyzed from infarcted tissue by using RNA sequencing analysis. The inflammatory response after I/R was evaluated by flow cytometry. Heart function was assessed by echocardiography and fibrosis by Masson’s trichrome staining. Transcriptome and gene set enrichment analysis revealed a modulation of the inflammatory response upon administration of the Wnt secretion inhibitor LGK-974 following I/R. In addition, LGK-974-treated animals showed an attenuated inflammatory response and improved heart function. In an in vitro model of hypoxic cardiomyocyte and monocyte/macrophage interaction, LGK974 inhibited the activation of Wnt signaling in monocytes/macrophages and reduced their pro-inflammatory phenotype. We here show that Wnt signaling affects inflammatory processes after MI. The Wnt secretion inhibitor LGK-974 appears to be a promising compound for future immunomodulatory approaches to improve cardiac remodeling after MI.

Wavelet-based entropy and complexity to identify cardiac electrical instability in patients post myocardial infarction

Myocardial infarction (MI) has been long recognized as the main cause of malignant ventricular arrhythmia and/or sudden cardiac death. The region of myocardial scars is related to conduction abnormalities that are rejected as fragmentation of the QRS complexes, which could persist several months after the acute event. In the present work, we evaluated the normalized entropy (H) and the statistical complexity (C) of QRS complexes, by using the continuous wavelet transform, as an effective method to quantify abnormal alterations in cardiac electrical activity in post-MI patients.We have included the standard 12-leads electrocardiogram (ECG) records of healthy subjects (CTRL), n = 48, and MI patients without ventricular tachycardia (VT) and/or fibrillation (VF), grouped in MI healing (MI7), n = 84, and healed (MI60), n = 41, phases.The mean H and C values (H‾ and C‾) of each subject were calculated. H‾ significantly increased and C‾ significantly decreased (p < 0.05) for MI7, and were sustained in MI60, with respect to CTRL. We integrated all the ECG leads in a single multi-lead criteria (H‾ML and C‾ML). Moreover, we separated MI patients according to the infarcted area in anterior and inferior subsets. H‾ML and C‾ML showed the same trends as H‾ and C‾ for total patients and both infarcted areas subsets, with the advantage that higher values of sensitivity and specificity were obtained.In conclusion, wavelet entropy and statistical complexity applied to ECG records give new insight into the analysis of patients post-MI, who have not suffered VT/VF, in both MI stages, independently of the infarction areas analyzed.

Time-dependent influence of infliximab on hemodynamic responses and cardiac injuries of isoproterenol-induced myocardial infarction in rats

Immune-induced inflammation plays an important role both in aggravating and healing of post myocardial infarction (MI) injuries. Potent anti-inflammatory and local immunomodulatory activity of infliximab has been suggested to have modulating effects on immune responses after MI. The aim of the present study was to evaluate the efficacy of infliximab on hemodynamic responses and myocardial injuries following isoproterenol-induced myocardial infarction. Male Wistar rats, weighting 260 ± 20 g were assigned into ten groups (n = 6) of saline (normal saline), infliximab (7 mg/kg), isoproterenol (100 mg/kg for two consecutive days), and isoproterenol plus infliximab (30 min after the second injection of isoproterenol). The heart tissues and serums were analyzed 24, 48, 72, and 96 h post-MI and hemodynamic parameters, histopathological changes, malondialdehyde (MDA), Total antioxidant capacity (TAC), lactate dehydrogenase (LDH), and lactate levels were assessed in the respective groups. Infliximab partially improved hemodynamic depression in the first days after MI, but the heart became more suppressed later. A similar result also obtained at the MDA tissue levels but not serum levels. Anti-inflammatory effects of Infliximab may improve cardiac function and prevent heart tissue injury early after MI; however, it can worsen the condition later by inhibiting compensatory reactions such as cardiac remodeling and tissue repair.

Abstract 14554: Angiogenic Agent Ono-1301 Enhanced Cardiac Contractile Proteins in Hipsc Derived Cardiac Tissue-like Construct With Functional Angiogenesis

Introduction: Transplantation of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) into myocardial infarcted areas has shown potential in healing myocardial infarction (MI). However, the survival rate of transplanted cells is yet considered limited, restricting the therapeutic effects of the transplantation. We assumed that adding angiogenic agent ONO-1301 could promote early stage angiogenesis between host and graft, and benefit the therapeutic effects of hiPSC-CM transplantation. Methods: This study is based on our former study of Cardiac Tissue-Like Construct (CTLC), where 5 x10e6 of hiPSC-CM was seeded on a 1x1cm poly(lactic-co-glycolic acid) (PLGA) nano fiber (Figure A). In addition, angiogenic agent ONO-1301 was mixed into the fibers. After 24h culture in vitro, 3 layers of CTLCs were transplanted into Nude rat MI models with or without ONO-1301. The rats were raised for another 4 or 8 weeks before sacrifice. Results: In vitro experiments have shown that supernatant of iPS-CM with ONO-1301 underwent a rise in VEGF during a 3 to 6 day culture (Figure B). The VEGF concentration in ONO-1301 positive group is much higer than ONO-1301 negative group (P=0.022) on day3. This difference narrows down over time. In vivo experiments on nude rat have shown that capillary density on MI border zone of ONO fiber+iPS-CM group is 29.95% higher than that of PLGA fiber+iPS-CM group (P=0.004) (figure C). HE and immunofluorescence staining shows remaining transplanted hiPSC-CMs in ONO fiber+iPS-CM group shows more significant TNT2 and human nuclear antigen(HNA) expression than that of PLGA fiber+iPS-CM group (Figure D and E). Also ONO fiber+iPS-CM group showed functional recovery compared to the sham.

The condition of neuro-endocrine systems in acute experimental myocardial infarction against the background of various reactivity of the organism

The adequacy of recovery processes in myocardial infarction (MI) significantly depends on the state of reactivity of the organism, which, in turn, is determined by the adequacy of neuro-endocrine regulation, in particular, hypothalamic-pituitary-adrenocortical (HPA) and hypothalamic-pituitary-thyroid (HPT) system system.Purpose of the study. To investigate the condition of HPA and HPT in acute experimental MI against the background of different reactivity of the organism.Material and methods. The study was performed on 20 outbred adult dogs weighing 8-12 kg, in which MI was simulated by ligation of the anterior interventricular artery. Animals were divided into three groups (n =5 in each group). The condition of hyperreactivity was caused by the introduction of pyrogenal (group 2), the state of hyporeactivity - the introduction of azothioprine (group 3), in group 1 drugs were not used (state of normoreactivity). In the control group used 5 falsely operated dogs with thoracopericardiotomy. In animals before surgery, on 1, 4, 7, 11 and 15 days in the blood was determined by the content of adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH) , cortisol (Cr), aldosterone (Ald), thyroxine and triiodothyronine. Statistical processing was performed using license packages Statistica 5.5 (Stat Soft Rus), Statistica Neural Networks (Statsoft Inc.).Results. Normoreactive course of myocardial infarction was characterized by primary activation of HPA, which was most pronounced for Cortisol, followed by restoration of ACTH and Aldosterone levels and duration of activation of the central link up to 4 days, peripheral - up to 7-11 days; reciprocal in relation to HPA inhibition of the functional activity of the HPT, most pronounced on the 4th day and lasting up to 15 days. Such changes caused the healing of myocardial infarction through the formation of a full-fledged post-infarction scar. The hyperreactive course of myocardial infarction was characterized by hypersecretion of ACTH with hypercorticism and hyperaldosteronism and less pronounced suppression of HPT with the restoration of its functional activity on the 7th day. The hyporeactive course of myocardial infarction was characterized by a minimally pronounced and delayed up to 4 days activation of HPA with Aldosterone hyposecretion on the 15th day; deep hypothyroidism of both central and peripheral genesis. Impaired reactivity was accompanied by an increase in the area of necrosis and a decrease in the thickness of the heart wall with the formation of postinfarction aneurysm.Conclusions. Desynchronization of necrotic and reparative processes with a change in reactivity leads to a disruption in the relationship between necrosis and repair with the formation of postinfarction aneurysm, which is accompanied by different activities of the HPA and HPT.

Early moderate exercise benefits myocardial infarction healing via improvement of inflammation and ventricular remodelling in rats.

Thus far, the cellular and molecular mechanisms related to early (especially within 24 hours after acute myocardial infarct (MI)) exercise‐mediated beneficial effects on MI have not yet been thoroughly established. In the present study, we demonstrated that acute MI rats that underwent early moderate exercise training beginning one day after MI showed no increase in mortality and displayed significant improvements in MI healing and ventricular remodelling, including an improvement in cardiac function, a decrease in infarct size, cardiomyocyte apoptosis, cardiac fibrosis and cardiomyocyte hypertrophy, and an increase in myocardial angiogenesis, left ventricular wall thickness and the number of cardiac telocytes in the border zone. Integrated miRNA‐mRNA profiling analysis performed by the ingenuity pathway analysis system revealed that the inhibition of the TGFB1 regulatory network, activation of leucocytes and migration of leucocytes into the infarct zone comprise the molecular mechanism underlying early moderate exercise‐mediated improvements in cardiac fibrosis and the pathological inflammatory response. The findings of the present study demonstrate that early moderate exercise training beginning one day after MI is safe and leads to significantly enhanced MI healing and ventricular remodelling. Understanding the mechanism behind the positive effects of this early training protocol will help us to further tailor suitable cardiac rehabilitation programmes for humans.

Model First and Ask Questions Later: Confessions of a Reformed Experimentalist.

This paper is an invited perspective written in association with the awarding of the 2018 American Society of Mechanical Engineers Van C. Mow Medal. Inspired by Professor Mow's collaboration with Professor Michael Lai and the role mathematical modeling played in their work on cartilage biomechanics, this article uses our group's work on myocardial infarct healing as an example of the potential value of models in modern experimental biomechanics. Focusing more on the thought process and lessons learned from our studies on infarct mechanics than on the details of the science, this article argues that the complexity of current research questions and the wealth of information already available about almost any cell, tissue, or organ should change how we approach problems and design experiments. In particular, this paper proposes that constructing a mathematical or computational model is now in many cases a critical prerequisite to designing scientifically useful, informative experiments.

EGF-like repeats and discoidin I-like domain 3 (EDIL3) deficiency improves post-myocardial infarction healing via neutrophil extracellular traps (NETs) mediated pro-inflammatory macrophage polarization

Abstract After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils, leading to extravasated monocytes polarized to inflammatory and reparative macrophages sequentially, which contribute to the healing and regenerative process. As an endogenous leukocyte-endothelial adhesion inhibitor, the role of EDIL3 in MI remains obscure. We found that serum EDIL3 level of MI patients was negatively associated with MI biomarkers, including CK-MB, cTnI and MGB. EDIL3−/− mice showed improved infarct healing with lower mortality, better cardiac function and decreased infarcted size compared with wild type (WT). Enhanced neutrophil infiltration resulted in the increase of Ly6Chi MHClo Mertk− macrophages, which we identified to be pro-inflammatory, protecting EDIL3−/− mice hearts from excessive fibrosis. A neutrophil infiltration antagonist not only eliminated the difference in cardiac function between WT and EDIL3−/− mice, but also reduced Ly6Chi MHClo Mertk− macrophage polarization. These data implied that improved cardiac healing was associated with increased infiltration of neutrophil and it mediated macrophage polarization. Notably, we confirmed that this polarization depended on NETs, which were more abundant in hearts and serum in EDIL3−/− mice than in WT. Indeed, self-DNA released from NETs primed the pro-inflammatory polarization of macrophages. The degradation of NETs by DNase I reduced this polarization and thus affected post-MI outcome, indicating the pivotal role of NETs in MI healing. Meanwhile, the pro-inflammatory macrophages induced apoptosis of neutrophils and restrained excessive inflammation. Our findings reveal a novel neutrophil–macrophage crosstalk essential to cardiac healing after MI.

Figures of the Heart Failure Association: Professor Dr. med. Johann Bauersachs, Chair of the Clinical Science Section.

Figures of the Heart Failure Association: Professor Dr. med. Johann Bauersachs, Chair of the Clinical Science Section.

Low Density Lipoprotein Receptor-Related Protein-1 in Cardiac Inflammation and Infarct Healing.

Acute myocardial infarction (AMI) leads to myocardial cell death and ensuing sterile inflammatory response, which represents an attempt to clear cellular debris and promote cardiac repair. However, an overwhelming, unopposed or unresolved inflammatory response following AMI leads to further injury, worse remodeling and heart failure (HF). Additional therapies are therefore warranted to blunt the inflammatory response associated with ischemia and reperfusion and prevent long-term adverse events. Low-density lipoprotein receptor-related protein 1 (LRP1) is a ubiquitous endocytic cell surface receptor with the ability to recognize a wide range of structurally and functionally diverse ligands. LRP1 transduces multiple intracellular signal pathways regulating the inflammatory reaction, tissue remodeling and cell survival after organ injury. In preclinical studies, activation of LRP1-mediated signaling in the heart with non-selective and selective LRP1 agonists is linked with a powerful cardioprotective effect, reducing infarct size and cardiac dysfunction after AMI. The data from early phase clinical studies with plasma-derived α1-antitrypsin (AAT), an endogenous LRP1 agonist, and SP16 peptide, a synthetic LRP1 agonist, support the translational value of LRP1 as a novel therapeutic target in AMI. In this review, we will summarize the cellular and molecular bases of LRP1 functions in modulating the inflammatory reaction and the reparative process after injury in various peripheral tissues, and discuss recent evidences implicating LRP1 in myocardial inflammation and infarct healing.

Conditioned media derived from mesenchymal stem cell cultures: The next generation for regenerative medicine.

Recent studies suggest that the main driving force behind the therapeutic activity observed in mesenchymal stem cells (MSCs) are the paracrine factors secreted by these cells. These biomolecules also trigger antiapoptotic events to prevent further degeneration of the diseased organ through paracrine signalling mechanisms. In comparison with the normal physiological conditions, an increased paracrine gradient is observed within the peripheral system of diseased organs that enhances the migration of tissue-specific MSCs towards the site of infection or injury to promote healing. Thus, upon administration of conditioned media derived from mesenchymal stem cell cultures (MSC-CM) could contribute in maintaining the increased paracrine factor gradient between the diseased organ and the stem cell niche in order to speed up the process of recovery. Based on the principle of the paracrine signalling mechanism, MSC-CM, also referred as the secretome of the MSCs, is a rich source of the paracrine factors and are being studied extensively for a wide range of regenerative therapies such as myocardial infarction, stroke, bone regeneration, hair growth, and wound healing. This article highlights the current technological applications and advances of MSC-CM with the aim to appraise its future potential as a regenerative therapeutic agent.

Glucagon-like peptide-1 receptor expression after myocardial infarction: Imaging study using 68Ga-NODAGA-exendin-4 positron emission tomography

BackgroundActivation of glucagon-like peptide-1 receptor (GLP-1R) signaling protects against cardiac dysfunction and remodeling after myocardial infarction (MI). The aim of the study was to evaluate 68Ga-NODAGA-exendin-4 positron emission tomography (PET) for assessment of GLP-1R expression after MI in rats. Methods and ResultsRats were studied at 3 days, 1 and 12 weeks after permanent coronary ligation or a sham-operation. Rats were injected with 68Ga-NODAGA-exendin-4 and scanned with PET and contrast-enhanced computed tomography (CT) followed by digital autoradiography and histology of left ventricle tissue sections. 68Ga-NODAGA-exendin-4 PET/CT showed focally increased tracer uptake in the infarcted regions peaking at 3 days and continuing at 1 week after MI. Pre-treatment with an unlabeled exendin-4 peptide significantly reduced 68Ga-NODAGA-exendin-4 uptake. By autoradiography, 68Ga-NODAGA-exendin-4 uptake was 8.6-fold higher in the infarcted region and slightly increased also in the remote, non-infarcted myocardium at 1 week and 12 weeks post-MI compared with sham. Uptake of 68Ga-NODAGA-exendin-4 correlated with the amount of CD68-positive macrophages in the infarcted area and alpha-smooth muscle actin staining in the remote myocardium. Conclusions68Ga-NODAGA-exendin-4 PET detects up-regulation of cardiac GLP-1R expression during healing of MI in rats and may provide information on the activated repair mechanisms after ischemic myocardial injury.