Recent Advance on Drug Therapy Related to Myocardial Ischemia Reperfusion Injury

Myocardial ischemia reperfusion injury (MIRI) means complete or partial artery obstruction of coronary artery, and ischemic myocardium will be recirculating in a period of time. Although the ischemic myocardium can be restored to normal perfusion, its tissue damage will instead be progressive. An aggravated pathological process. MIRI is a complex entity where many inflammatory mediators play different roles, both to enhance myocardial infarction-derived damage and to heal injury. Therefore, the research and development of drugs for the prevention and treatment of this period has also become the focus. This article first studied pathophysiology of MIRI, and reviewed the research progress of MIRI-related drugs. Research results show that: MIRI is inevitable for myocardial ischemia, with the possible to double damage via the ischemic condition. Therefore, it is a serious complication and one of the most popular diseases in the world. It has always been difficult to find an effective treatment for this disease, because it is difficult to explore the inflammation behind its pathophysiology.

Tregs Biomimetic Nanoparticle to Reprogram Inflammatory and Redox Microenvironment in Infarct Tissue to Inhibit the Remodeling of the Left Ventricle of Myocardial Ischemia Reperfusion Injury in Mice

Background At present, patients with myocardial infarction remain an increased risk for myocardial ischemia/reperfusion injury (MI/RI), which currently lacks an effective therapeutic method. It is still a bottleneck that effectively deliver drug to ischemic myocardium to treat MI/RI. Inspired by the protective effect of regulatory T cells (Tregs) on MI/RI and natural role of platelets in adhesion with damaged blood vessel in heart during myocardial infarct, a Tregs biomimetic nanoparticle (CsA@PPTK) was prepared by camouflaging a cyclosporin A (CsA)-loaded and reactive oxygen species (ROS)-sensitive nanoparticle with platelet membrane. Results In MI/RI mice, CsA@PPTK could be preferentially delivered to ischemic myocardium. CsA@PPTK significantly scavenged ROS in ischemic myocardium, while it also markedly increased the generation of Tregs and the ratio of M2 type macrophage to M1 type macrophage in ischemic myocardium. Furthermore, CsA@PPTK significantly attenuated apoptosis of cardiomyocytes in ischemic myocardium. At the same time, CsA@PPTK obviously reduced the infarct size, fibrosis area and the protein expression of MMP-9, while increased the protein expression of CX43. Subsequently, the remodeling of the left ventricle was significant alleviated. Finally, heart function of MI/RI mice was markedly improved. Conclusion CsA@PPTK has great potential in the treatment of MI/RI. This study provides a novel class of heart protective biomimetic platform that is beneficial for treatment of MI/RI.

Fractal structure of cardiovascular system

The structure of different systems, aiming to supply a volume of definite tissue with a specific fluid, which is for example the blood in the vascular system, obeys on similar lows, which can be expressed by mathematical equations. Those systems have fractal structure, that means every small part of the system repeats the structure of entire system. Knowing those dependencies permits calculation of one particular parameter of cardiovascular system, for example, the amount of myocardium on the basis of diameter of coronary artery supplying it. This approach is extremely applicable to the patients with coronary artery disease, where the amount of ischemic myocardium is of paramount importance for the patient`s fate. The aim of the current review is to present the main interdependencies between anatomical and physiological parameters of cardiovascular system.

Possibilities of pharmacological correction of reperfusion injury of ischemic myocardium (review)

Timely and effective reperfusion in ischemia and reoxygenation in hypoxia of the heart muscle prevent myocardial infarction. Delayed reperfusion and reoxygenation in myocardial ischemia and hypoxia can cause reversible damage in it, which, with a favorable outcome, disappear without a trace. Excessively late reperfusion and reoxygenation inevitably ends with irreversible damage to the myocardium, which is widely known as a myocardial infarction, and which, together with other complications of cardiac ischemia, can cause disability and death of the patient. In recent years, reperfusion injury of the ischemic heart muscle has been recognized as an independent link in the pathogenesis of myocardial infarction. The mechanisms of this link of pathogenesis have been partially studied in experimental conditions. The phenomena of preconditioning and post-conditioning have been discovered, the effects of which are currently determined fairly reliably. After determining the mechanisms of reperfusion injury of the ischemic myocardium, the search and development of pharmacological agents capable of inducing such a phenomenon as cardioprotection began. In parallel, studies of specific microRNAs that claim to be diagnostic markers are being conducted, as well as the search for drugs that affect the level of their expression is being conducted. The information about the achieved successes in this direction is given.

Lactobacillus plantarum Probiotic Induces Nrf2-mediated Antioxidant Signaling and eNOS Expression Resulting in Improvement of Myocardial Diastolic Function

Yorkshire swine were fed standard diet (n=7) or standard diet containing caffeic acid with L. plantarum (n=7) for three weeks. Next, an ameroid constrictor was placed around the left coronary circumflex artery, and the dietary regimens were continued. At fourteen weeks, cardiac function, myocardial perfusion, vascular density, and molecular signaling in ischemic myocardium were evaluated.The L. plantarum-caffeic acid augmented Nrf2 in the ischemic myocardium, and induced Nrf2-regulated antioxidant enzymes heme oxygenase-1 (HO-1), NADPH dehydrogenase quinone 1 (NQO-1), and thioredoxin reductase (TRXR-1). Improved left ventricular diastolic function and decreased myocardial collagen expression were seen in animals receiving the L. plantarum-caffeic acid supplements. The expression of endothelial nitric oxide synthase (eNOS) was increased in ischemic myocardial tissue of the treatment group, while levels of asymmetric dimethyl arginine (ADMA), hypoxia inducible factor 1α (HIF-1α), and phosphorylated MAPK (pMAPK) were decreased. Collateral dependent myocardial perfusion was unaffected while arteriolar and capillary densities were reduced as determined by a-smooth muscle cell actin and CD31 immunofluorescence in ischemic myocardial tissue. Dietary supplementation with L. plantarum and caffeic acid is a safe and effective method of enhancing Nrf2-mediated antioxidant signaling cascade in ischemic myocardium. Although this experimental diet was associated with a reduction in hypoxic stimuli, decreased vascular density and without any change in collateral-dependent perfusion, the net effect of an increase in antioxidant activity and eNOS expression resulted in improvement in diastolic function.

Abstract 118: Interleukin 4 And 13 Signaling In Macrophages Regulates Neonatal Cardiac Regeneration

Introduction: Heart failure (HF) is a prevalent disease, projected to affect over 8 million Americans by 2030. Current therapy partially decreases progression; however, mortality and disease burden continue to be high. Therefore, there is an unmet need to develop new strategies that target HF progression. Our lab employs the neonatal mouse model of cardiac regeneration to identify pro-reparative pathways that can be applied to treating HF in humans. Previously we demonstrated that the anti-inflammatory cytokine, Interleukin 13 (IL13), promotes cardiac regeneration, however, the cell types mediating this response remain unknown. IL13 and the related cytokine, IL4, share a common receptor (IL4Rα) and both cytokines polarize macrophages into a reparative phenotype. Here, we hypothesize that IL4/13 signaling to macrophages promotes heart regeneration after cardiac injury and we explore the cell source of these cytokines during neonatal development and cardiac regeneration. Methods and Results: We generated a genetic model whereby IL4Rα is depleted in macrophages by crossing IL4Rα floxed (IL4Rα fl/fl ) mice with transgenic mice CX3Cr1 driven-Cre recombinase (CX3CR1 Cre ). Flow cytometry analysis confirmed depletion of IL4Rα in cardiac macrophages. We performed myocardial infarction (MI) on postnatal day 1 (P1) mice and assessed cardiac regeneration by ultrasonography 21 days post-injury (dpi). We found that IL4Rα fl/fl CX3CR1 Cre mice had lower ejection fraction compared to IL4Rα fl/fl littermate controls. Preliminary results suggest there is a reduced capillary density in peri-ischemic myocardium. In addition, we used fluorescent reporter mouse lines; IL4-enhanced green fluorescent protein (IL4-GFP) and IL13-yellow fluorescent protein (IL13-YFP), to assess the cellular source of IL4 and IL13 expression in the hearts of neonatal mice. In unoperated mice, we found no detectable expression of IL13 by any cell type in the heart, whereas IL4 was expressed in innate lymphoid cells (ILCs) and T cells. 4 days after MI in P1 mice IL13 was upregulated in ILCs and T cells and IL4 was expressed by ILCs and T cells and upregulated in myeloid cells. Conclusions and Discussion: We found that IL13 and IL4 are primarily expressed in ILCs and T cells following neonatal injury, suggesting a novel role for ILCs and T cells in the production of IL4 and 13 during the neonatal regeneration process. In addition, we found that lack of IL4/13 signaling in macrophages via depletion IL4Rα impairs cardiac regeneration after MI in neonatal mice, and results in reduced capillary density in peri-ischemic myocardium. We hypothesize that IL4Rα depletion in macrophages impairs reparative macrophage polarization after MI and promotes an inflammatory polarization. Future studies will be aimed to assess macrophage phenotypes in response to IL13/IL4 signaling by transcriptional profiling and flow cytometry.

Abstract P375: Gender-based Cardio-protective Functional Dimorphism Of Bone Marrow Endothelial Progenitor Cells And Their Exosomes: Estrogen-independent Epigenetic Mechanisms

Introduction: Estrogen or estrogen receptor-dependent mechanisms in enhancing the cardioprotective efficacy of bone marrow endothelial progenitor cells (BM-EPC) is well-established in preclinical studies. However, the efficacy of estrogen does not reflect in the data from randomized cardiovascular clinical trials, suggesting an estrogen-independent role of female BM-EPC in eliciting enhanced cardiac protection compared to males. Hypothesis: Epigenetic mechanisms may contribute to the sex-specific dimorphism of Sca-1 + /CD31 + BM-EPC in regulating cell-homing, pro-angiogenic and anti-inflammatory functions in the ischemic myocardium leading to enhanced reparative function of female progenitor cells. Methods & Results: Transplantation of GFP-BM-mononuclear cells from male and female GFP transgenic mice into the BM of lethally irradiated recipient male C57BL/6 mice resulted in the enhanced mobilization of female Sca-1 + CD31 + /GFP + BM-EPC into circulation post-MI. A higher number of female BM-EPC homed to the ischemic myocardium and significantly improved LV functions and capillary density post-MI compared to male BM-EPC. Female BM-EPC showed increased expression of bFGF, VEGFR2, SDF-1α, and IL-10 genes, thereby efficiently promoted endothelial tube formation in vitro compared to male BM-EPC. Transplantation of female BM-EPC and their exosomes into post-MI male mice improved LV cardiac function, reduced scar size, and improved capillary density compared to male BM-EPC and exosomes. Male BM-EPC showed an increased expression of G9a/Ehmt2, an H3K9me3 methyltransferase, and Dnmt3a DNA methyltransferase compared to female BM-EPC. In contrast, Kdm6b/JMJD3, H3K27me3 demethylase was highly expressed in female BM-EPC compared to males. Treatment of BM-EPC of both sexes with 17-β-estradiol did not alter the expression of Kdm6b/JMJD3. Male BM-EPC highly expressed repressive gene marks, H3K9me3, and H3K27me3 compared to females. Compared to the male, BM-EPC from female and ovariectomized (OXV) female mice showed equally high expression of angiogenic genes ANGPT-1, MDK, PLAU, Tie-2, and VEGFR2 and lower levels of inflammatory cytokines, TNFα, IFNγ, IL-1β, and CCL3. Conditioned medium from female and OVX BM-EPC equally promoted enhanced migration and tube formation of HUVEC in vitro, compared to male BM-EPC. Conclusions: An estrogen-independent epigenetic mechanism likely governs the enhanced cardiac reparative properties of female BM-EPC.

Hepatic cell mobilization for protection against ischemic myocardial injury

The heart is capable of activating protective mechanisms in response to ischemic injury to support myocardial survival and performance. These mechanisms have been recognized primarily in the ischemic heart, involving paracrine signaling processes. Here, we report a distant cardioprotective mechanism involving hepatic cell mobilization to the ischemic myocardium in response to experimental myocardial ischemia–reperfusion (MI-R) injury. A parabiotic mouse model was generated by surgical skin-union of two mice and used to induce bilateral MI-R injury with unilateral hepatectomy, establishing concurrent gain- and loss-of-hepatic cell mobilization conditions. Hepatic cells, identified based on the cell-specific expression of enhanced YFP, were found in the ischemic myocardium of parabiotic mice with intact liver (0.2 ± 0.1%, 1.1 ± 0.3%, 2.7 ± 0.6, and 0.7 ± 0.4% at 1, 3, 5, and 10 days, respectively, in reference to the total cell nuclei), but not significantly in the ischemic myocardium of parabiotic mice with hepatectomy (0 ± 0%, 0.1 ± 0.1%, 0.3 ± 0.2%, and 0.08 ± 0.08% at the same time points). The mobilized hepatic cells were able to express and release trefoil factor 3 (TFF3), a protein mitigating MI-R injury as demonstrated in TFF3−/− mice (myocardium infarcts 17.6 ± 2.3%, 20.7 ± 2.6%, and 15.3 ± 3.8% at 1, 5, and 10 days, respectively) in reference to wildtype mice (11.7 ± 1.9%, 13.8 ± 2.3%, and 11.0 ± 1.8% at the same time points). These observations suggest that MI-R injury can induce hepatic cell mobilization to support myocardial survival by releasing TFF3.