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We investigated whether miR143#12, a synthesized chemically modified miR-143-3p derivative, exerts therapeutic effects on acute myocardial infarction (AMI). Sprague-Dawley rats and Japanese white rabbits underwent 30 min of coronary occlusion followed by 2 weeks of reperfusion. The rat AMI model was intravenously administered with control miRNA (9 μg/kg), 3 μg/kg or 9 μg/kg of miR143#12 1 h after reperfusion, while the rabbit AMI model was intravenously administered with control miRNA (9 μg/kg) or 9 μg/kg of miR143#12. In the rat and rabbit AMI models, 9 μg/kg of miR143#12 significantly reduced infarct sizes and significantly improved cardiac function including LVEF and LVFS at 2 weeks. The tissue miR143 levels in infarct areas significantly decreased after AMI in both models. Electron microscopic study and immunohistochemistry suggested that miR143#12 suppressed autophagic cell death caused by AMI and induced neoangiogenesis in the infarct border. In cultured rat H9c2 cells, miR143#12 significantly inhibited H 2 O 2 -induced autophagic cell death by decreasing ROS levels and increased viable cell numbers more than the control by silencing COX-1, -2, and ATG7. Replacement treatment with miR143#12 in the infarct areas, where the expression levels of miR143 were significantly decreased, has a beneficial effect on AMI by silencing COX-1 and -2., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Progranulin is a secreted glycoprotein that regulates inflammation and wound healing. However, plasma progranulin levels in the acute phase and their clinical significance in patients with acute myocardial infarction (AMI) remain to be elucidated., Objective: We aimed to investigate the relationship between the increase in plasma progranulin levels in the acute phase and the recovery of left ventricular function in the chronic phase in AMI patients., Method and Result: Eighteen AMI patients were followed up for 6 months. Blood samples were collected from the antecubital vein on day 0 (on admission) and day 7 in the acute phase. The control group consisted of patients without significant coronary artery stenosis, as assessed by cardiac catheterization (n = 16). Plasma progranulin levels were measured by enzyme-linked immunosorbent assay. Echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI to evaluate left ventricular ejection fraction using the modified Simpson's method. Plasma progranulin levels in the AMI group on day 0 (69.5 ± 24.6 ng/mL) were similar to those in the control group (84.2 ± 47.1 ng/mL). There was a significant increase in progranulin levels in the AMI group on day 7 (104.2 ± 52.0 ng/mL) compared with day 0. The increase in plasma progranulin levels in the acute phase was positively correlated with the increase in left ventricular ejection fraction between the acute and chronic phases. Among various factors, only plasma progranulin levels were favorably correlated with left ventricular functional recovery in the chronic phase., Conclusion: The increase in plasma progranulin levels in the acute phase may serve as a predictive biomarker and a contributer for the recovery of left ventricular function in the chronic phase in patients with AMI., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Minatoguchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Percutaneous coronary intervention (PCI) of calcified lesions remains challenging for interventionalists., Aims: We aimed to investigate whether combining rotational atherectomy (RA) with cutting balloon angioplasty (RA+CBA) results in more optimal stent expansion compared with RA followed by non-compliant balloon angioplasty (RA+NCBA)., Methods: ROTA-CUT is a prospective, multicentre, randomised trial of 60 patients with coronary artery disease undergoing PCI of moderately or severely calcified lesions with drug-eluting stent implantation. Patients were randomised 1:1 to either RA+CBA or RA+NCBA. The primary endpoint was the minimum stent area on intravascular ultrasound (IVUS). Secondary endpoints included minimum lumen area and stent expansion assessed by IVUS and acute lumen gain, final residual diameter stenosis and minimum lumen diameter assessed by angiography. Clinical endpoints were obtained at 30 days., Results: The mean age was 71.1±9.4 years, and 22% were women. The procedural details of RA were similar between groups, as were procedure duration and contrast use. Minimum stent area was similar with RA+CBA versus RA+NCBA (6.7±1.7 mm 2 vs 6.9±1.8 mm 2 ; p=0.685). Furthermore, there were no significant differences regarding the other IVUS and angiographic endpoints. Procedural complications were rare, and 30-day clinical events included 2 myocardial infarctions and 1 target vessel revascularisation in the RA+CBA group and 1 myocardial infarction in the RA+NCBA group., Conclusions: Combining RA with CBA resulted in a similar minimum stent area compared with RA followed by NCBA in patients undergoing PCI of moderately or severely calcified lesions. RA followed by CBA was safe with rare procedural complications and few clinical adverse events at 30 days.

Background: MicroRNA (miR)-143 and miR-145 are non-coding RNAs present in smooth muscle cells and the heart. However, their behavior and physiological role in patients with acute myocardial infarction (AMI) have not been clarified., Methods and results: Plasma miR-143 and miR-145 concentrations were measured on Day 0 (on admission) and on Day 7 in AMI patients who could be followed up for 6 months (n=25). The control group consisted of subjects without significant coronary stenosis (n=20). Blood samples were collected from the antecubital vein, and plasma miR-143 and miR-145 concentrations were measured by quantitative reverse transcription-polymerase chain reaction. In AMI patients (n=25), left ventricular ejection fraction (LVEF) was measured by echocardiography in the acute and chronic (6 months) phases. On Day 7, plasma miR-143 and miR-145 concentrations were significantly higher in AMI patients than in the control group and on Day 0 in AMI patients. Plasma miR-143 and miR-145 concentrations increased significantly from Day 0 to Day 7. The increase in plasma miR-143 concentrations (∆miR-143) in the acute phase was positively correlated with the increase in LVEF in the chronic phase. Among many factors, only ∆miR-143 was favorably correlated with left ventricle (LV) functional recovery in the chronic phase., Conclusions: An increase in plasma miR-143 concentrations in the acute phase may be a biomarker predicting recovery of LV function in the chronic phase in AMI patients.

Rapid percutaneous coronary intervention for acute myocardial infarction (AMI) reduces acute mortality, but there is an urgent need for treatment of left ventricular dysfunction and remodeling after AMI to improve the prognosis. The myocardium itself does not have a high regenerative capacity, and it is important to minimize the loss of cardiomyocytes and maintain the cardiac function after AMI. To overcome these problems, attention has been focused on myocardial regeneration therapy using cells derived from bone marrow. The clinical use of bone marrow stem cells is considered to have low safety concerns based on the experience of using bone marrow transplantation for blood diseases in clinical practice. It has been reported that bone marrow mononuclear cells (BM-MNC) and mesenchymal stem cells (BM-MSC) differentiate into cardiomyocytes both in vitro and in vivo, and they have been considered a promising source for stem cell therapy. To prevent heart failure after human AMI, studies have been conducted to regenerate myocardial tissue by transplanting bone marrow stem cells, such as BM-MSCs and BM-MNCs. Therapies using those cells have been administered to animal models of AMI, and were effective to some extent, but the effect in clinical trials was limited. Recently, it was reported that multilineage-differentiating stress enduring cells (Muse cells), which are endogenous pluripotent stem cells obtainable from various tissues including the bone marrow, more markedly reduced the myocardial infarct size and improved the cardiac function via regeneration of cardiomyocytes and vessels and paracrine effects compared with BM-MSCs. Here, we describe stem cell therapies using conventional BM-MNCs and BM-MSCs, and Muse cells which have potential for clinical use for the treatment of AMI., (Copyright © 2021. Published by Elsevier Ltd.)

Background: We recently reported that multilineage-differentiating stress enduring (Muse) cells intravenously administered after acute myocardial infarction (AMI), selectively engrafted to the infarct area, spontaneously differentiated into cardiomyocytes and vessels, reduced the infarct size, improved the left ventricular (LV) function and remodeling in rabbits. We aimed to clarify the efficiency of Muse cells in a larger animal AMI model of mini-pigs using a semi-clinical grade human Muse cell product., Method and Result: Mini-pigs underwent 30 min of coronary artery occlusion followed by 2 weeks of reperfusion. Semi-clinical grade human Muse cell product (1x107, Muse group, n = 5) or saline (Vehicle group, n = 7) were intravenously administered at 24 h after reperfusion. The infarct size, LV function and remodeling were evaluated by echocardiography. Arrhythmias were evaluated by an implantable loop recorder. The infarct size was significantly smaller in the Muse group (10.5±3.3%) than in the Vehicle group (21.0±2.0%). Both the LV ejection fraction and fractional shortening were significantly greater in the Muse group than in the Vehicle group. The LV end-systolic and end-diastolic dimensions were significantly smaller in the Muse group than in the Vehicle group. Human Muse cells homed into the infarct border area and expressed cardiac troponin I and vascular endothelial CD31. No arrhythmias and no blood test abnormality were observed., Conclusion: Muse cell product might be promising for AMI therapy based on the efficiency and safety in a mini-pig AMI., Competing Interests: The authors have declared that no competing interests exist.

Background: Changes in the plasma adenosine concentration and the effects on left ventricular (LV) function and remodeling in patients with acute myocardial infarction (AMI) remain unclear., Methods and results: In 58 patients with AMI and 14 subjects without cardiac disease (controls), we measured the plasma adenosine concentration by LC-MS/MS. Blood samples were taken from the antecubital vein on days 0, 1, 7, and 14 after AMI, and from the controls on admission. Cardiac echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI. There were no significant differences in the plasma adenosine concentrations among days 0 (211.5±150.2 nmol/L), 1 (192.7±141.3 nmol/L), 7 (218.8±154.1 nmol/L), and the controls (136.0±50.9 nmol/L). The plasma adenosine concentration increased significantly on day 14 (321.1±195.4 nmol/L) after AMI as compared with days 0, 1 and 7. AMI patients with a greater increase in the plasma adenosine concentration in the subacute phase showed an attenuation of LV dilation in the chronic phase. The plasma adenosine concentration in the acute phase did not affect the LV ejection fraction in the chronic phase., Conclusions: The plasma adenosine concentration significantly increased 14 days after AMI, which may contribute to attenuation of LV dilation in the chronic phase.

We investigated whether combination therapy of G-CSF and erythropoietin (EPO)-liposome with Siaryl Lewis X (SLX) is more cardioprotective than G-CSF or EPO-liposome with SLX alone. For the purpose of generating myocardial infarction (MI), rabbits underwent 30 minutes of coronary occlusion and 14 days of reperfusion. We administered saline (control group, i.v.,), G-CSF (G group, 10 μg/kg/day × 5 days, i.c., starting at 24 hours after reperfusion), EPO-liposome with SLX (LE group, i.v., 2500 IU/kg EPO containing liposome with SLX, immediately after reperfusion), and G-CSF + EPO-liposome with SLX (LE + G group) to the rabbits. The MI size was the smallest in the LE+G group (14.7 ± 0.8%), and smaller in the G group (22.4 ± 1.5%) and LE group (18.5 ± 1.1%) than in the control group (27.8 ± 1.5%). Compared with the control group, the cardiac function and remodeling of the G, LE, and LE + G groups were improved, and LE + G group tended to show the best improvement. The number of CD31-positive microvessels was the greatest in the LE + G group, greater in the G and LE groups than in the control group. Higher expressions of phosphorylated (p)-Akt and p-ERK were observed in the ischemic area of the LE and LE + G groups. The number of CD34 + /CXCR4 + cells was significantly higher in the G and LE + G groups. The cardiac SDF-1 was more expressed in the G and LE + G groups. In conclusion, Post-MI combination therapy with G-CSF and EPO-liposome with SLX is more cardioprotective than G-CSF or EPO-liposome with SLX alone through EPCs mobilization, neovascularization, and activation of prosurvival signals.

Rationale: Multilineage-differentiating stress enduring (Muse) cells, pluripotent marker stage-specific embryonic antigen-3 + cells, are nontumorigenic endogenous pluripotent-like stem cells obtainable from various tissues including the bone marrow. Their therapeutic efficiency has not been validated in acute myocardial infarction., Objective: The main objective of this study is to clarify the efficiency of intravenously infused rabbit autograft, allograft, and xenograft (human) bone marrow-Muse cells in a rabbit acute myocardial infarction model and their mechanisms of tissue repair., Methods and Results: In vivo dynamics of Nano-lantern-labeled Muse cells showed preferential homing of the cells to the postinfarct heart at 3 days and 2 weeks, with ≈14.5% of injected GFP (green fluorescent protein)-Muse cells estimated to be engrafted into the heart at 3 days. The migration and homing of the Muse cells was confirmed pharmacologically (S1PR2 [sphingosine monophosphate receptor 2]-specific antagonist JTE-013 coinjection) and genetically (S1PR2-siRNA [small interfering ribonucleic acid]-introduced Muse cells) to be mediated through the S1P (sphingosine monophosphate)-S1PR2 axis. They spontaneously differentiated into cells positive for cardiac markers, such as cardiac troponin-I, sarcomeric α-actinin, and connexin-43, and vascular markers. GCaMP3 (GFP-based Ca calmodulin probe)-labeled Muse cells that engrafted into the ischemic region exhibited increased GCaMP3 fluorescence during systole and decreased fluorescence during diastole. Infarct size was reduced by ≈52%, and the ejection fraction was increased by ≈38% compared with vehicle injection at 2 months, ≈2.5 and ≈2.1 times higher, respectively, than that induced by mesenchymal stem cells. These effects were partially attenuated by the administration of GATA4 -gene-silenced Muse cells. Muse cell allografts and xenografts efficiently engrafted and recovered functions, and allografts remained in the tissue and sustained functional recovery for up to 6 months without immunosuppression., Conclusions: Muse cells may provide reparative effects and robust functional recovery and may, thus, provide a novel strategy for the treatment of acute myocardial infarction., (© 2018 American Heart Association, Inc.)

Background: Multilineage differentiating stress-enduring (Muse) cells are SSEA3 + and CD105 + double-positive pluripotent-like stem cells. We aimed to examine the mobilization of Muse cells into peripheral blood after acute myocardial infarction (AMI) and their effects on left ventricular (LV) function and remodeling., Methods and results: In 79 patients with AMI, 44 patients with coronary artery disease (CAD), and 64 normal subjects (Control), we measured the number of Muse cells in the peripheral blood by fluorescence-activated cell sorting. Muse cells were measured on days 0, 1, 7, 14, and 21 after AMI. Plasma sphingosine-1-phosphate (S1P) levels were measured. Cardiac echocardiography was performed in the acute (within 7 days) and chronic (6 months) phases of AMI. Muse cell number on day 1 was significantly higher in the AMI (276±137 cells/100 μL) than in the CAD (167±89 cells/100 μL) and Control (164±125 cells/100 μL) groups. Muse cell number peaked on day 1, and had gradually decreased on day 21. Muse cell number positively correlated with plasma S1P levels. Patients with a higher increase in the number of Muse cells in the peripheral blood but not those with a lower increase in number of Muse cells in the acute phase showed improved LV function and remodeling in the chronic phase., Conclusions: Endogenous Muse cells were mobilized into the peripheral blood after AMI. The number of Muse cells could be a predictor of prognosis in patients with AMI.

Acute myocardial infarction (AMI) is a common cause of morbidity and mortality worldwide. Severe MI leads to heart failure due to a marked loss of functional cardiomyocytes. First-line treatment for AMI is to reperfuse the occluded coronary artery by PCI as soon as possible. Besides PCI, there are several therapies to reduce the infarct size and improve the cardiac function and remodeling. These are drug therapies such as pharmacological pre- and postconditioning, cytokine therapies, and stem cell therapies. None of these therapies have been clinically developed as a standard treatment for AMI. Among many cell sources for stem cell therapies, the Muse cell is an endogenous non-tumorigenic pluripotent stem cell, which is able to differentiate into cells of all three germ layers from a single cell, suggesting that the Muse cell is a potential cell source for regenerative medicine. Endogenous Muse cell dynamics in the acute phase plays an important role in the prognosis of AMI patients; AMI patients with a higher number of Muse cells in the peripheral blood in the acute phase show more favorable improvement of the cardiac function and remodeling in the chronic phase, suggesting their innate reparative function for the heart. Intravenously administered exogenous Muse cells engrafted preferentially and efficiently to infarct border areas via the S1P-S1PR2 axis and differentiated spontaneously into working cardiomyocytes and vessels, showed paracrine effects, markedly reduced the myocardial infarct size, and delivered long-lasting improvement of the cardiac function and remodeling for 6 months. These findings suggest that Muse cells are reparative stem cells, and thus their clinical application is warranted.

We investigated whether microRNA-145 (miR-145) has a cardioprotective effect in a rabbit model of myocardial infarction (MI) and in H9c2 rat cardiomyoblasts. Rabbits underwent 30 min of coronary occlusion, followed by 2 days or 2 wk of reperfusion. Control microRNA (control group; 2.5 nmol/kg, n = 10) or miR-145 (miR-145 group, 2.5 nmol/kg, n = 10) encapsulated in liposomes was intravenously administered immediately after the start of reperfusion. H9c2 rat cardiomyoblasts were transfected with miR-145. The MI size was significantly smaller in the miR-145 group than in the control group at 2 days and 2 wk post-MI. miR-145 had improved the cardiac function and remodeling at 2 wk post-MI. These effects were reversed by chloroquine. Western blot analysis showed that miR-145 accelerated the transition of LC3B I to II and downregulated p62/SQSTM1 at 2 days or 2 wk after MI, but not at 4 wk, and activated Akt in the ischemic area at 2 days after MI. miR-145 inhibited the growth of H9c2 cells, accelerated the transition of LC3B I to II, and increased phosphorylated Akt in the H9c2 cells at 2 days after miR-145 transfection. Antagomir-145 significantly abolished the morphological change, the transition of LC3B I to II, and the increased phosphorylated Akt induced by miR-145 in H9c2 cells. We determined fibroblast growth factor receptor substrate 2 mRNA to be a target of miR-145, both in an in vivo model and in H9c2 cells. In conclusion, post-MI treatment with miR-145 protected the heart through the induction of cardiomyocyte autophagy by targeting fibroblast growth factor receptor substrate 2., (Copyright © 2015 the American Physiological Society.)

Background: Multilineage-differentiating stress-enduring (Muse) cells, which have a high potential for pluripotency, reside in the bone marrow (BM). Purpose: To clarify the efficiency of S1PR2 agonist to mobilizes endogenous Muse cells into peripheral blood from the BM for tissue repair after AMI. Methods: Japanese white rabbits underwent 30 min of coronary occlusion and 2 weeks of reperfusion. S1PR2 agonist SID46371153 (10 mg/kg, s.c.) or vehicle was administered at 30 min after reperfusion. The number of SSEA3+ and CD44+ double positive Muse cells in the peripheral blood was measured by FACS at 12 h after AMI. Results: The number of Muse cells in the blood significantly increased in the S1PR2 agonist group than in the control and sham groups. The number of Muse cells was the highest in the S1PR2 agonist group (320±62/100 μL) and higher in the vehicle group (208±53/100 μL) than in the sham group (78±20/100 μL). The number of Muse cells in the S1PR2 agonist group was decreased by S1PR2 antagonist to the level of vehicle group. The infarct size as a percentage of the left ventricle (LV) was significantly smaller in the S1PR2 agonist group (19.9±1.9%) than in the vehicle group (24.6±3.8%).The reduction in the infarct size in the S1PR2 agonist was blocked by S1PR2 antagonist (22.8±2.3%). S1PR2 antagonist by itself enlarged the MI size (26.6±1.4%). Functional recovery (EF, FS, ±dP/dt) in each group was correlated with the number of Muse cells. The increase in Muse cells number by S1PR2 agonist was completely abolished by S1PR2-specific antagonist JTE-013 (5 mg/kg, s.c.). Migration of Muse cells towards AMI serum and SID46371153 was pharmacologically (JTE-013) proven to be mediated through S1P-S1PR2 axis. Culture of peripheral blood mononuclear cells demonstrated the presence of Muse cells expressing Nanog, GATA4 and Nkx2.5, which differentiated into cardiomyocyte-like cells with positive troponin T and α-actinin, and endothelial-like cells with positive CD31. S1PR2 agonist significantly reduced the myocardial infarct size and improved LV function and remodeling as compared to the controls, which were completely abolished by JTE-013. S1PR2 agonist accelerated the homing of GFP+-Muse cells from the BM to the infarcted heart and expressed cardiac troponin-I, α-actinin, connexin 43 and CD31, suggesting the potential ability of endogenous Muse cells to differentiate into cardiomyocytes and microvessels. Conclusions: S1PR2 agonist is a mobilizer of endogenous Muse cells from the BM and might be a novel strategy for the regenerative therapy of AMI. [ABSTRACT FROM AUTHOR]

Background: Multilineage-differentiating stress-enduring (Muse) cells, which show high-level pluripotency, reside in the bone marrow (BM) as ~0.03% of the mononucleated fraction. We investigated whether intravenously administered human xenograft Muse cells could be mobilized to the ischemic myocardium, reduce the myocardial infarct size, and improve the cardiac function in a miniature pig model of AMI like the rabbit model. Methods: Using human BM-MSCs, Muse cells were collected as SSEA-3+ (xenograft Muse) cells by flow cytometry. In a 30-minute coronary occlusion and reperfusion model using miniature pigs (10kg), saline (vehicle group) and 1x107 of human xenograft Muse cells labeled with GFP (Muse group) were intravenously infused at 24 hours after MI. The MI size, cardiac function, and blood tests were evaluated at 2 weeks post-MI. We examined whether arrhythmia appeared using an ILR (implantable loop recorder) for 2 weeks. The general pathology of the heart was evaluated at 2 weeks post-MI. Confocal microscopy was performed to evaluate the regeneration of the myocardium. Results: The MI size measured using Masson trichrome staining was significantly smaller in the Muse group (10.5±3.3%) than in the vehicle group (20.5±2.3%) (P<0.05). At 2 weeks post-MI, a smaller left ventricular (LV) dimension and increased LV ejection fraction were seen in the Muse group as compared with the vehicle group with a statistically significant difference (P<0.05, P<0.001, respectively). Using the ILR, we confirmed that arrhythmias were not recorded in either group. The number of CD31-positive microvessels was significantly greater in regions surrounding the infarct area in the Muse group than in the vehicle group, suggesting that integrated Muse cells may have contributed to neovascularization. Integrated GFP(+)-Muse cells were positive for troponin I, suggesting the spontaneous differentiation of cardiomyocytes from Muse cells. Conclusions: The post-infarct intravenous administration of human xenograft Muse cells reduced the myocardial infarct size and improved cardiac remodeling and functioning through the regeneration of cardiomyocytes and microvessels in miniature pigs. Muse cell transplantation may be a promising strategy for AMI treatment. [ABSTRACT FROM AUTHOR]