Cardioprotective Effects of Puerarin-V on Isoproterenol-Induced Myocardial Infarction Mice Is Associated with Regulation of PPAR-Υ/NF-κB Pathway

Puerarin is a well-known traditional Chinese medicine which has been used for the treatment of cardiovascular diseases. Recently, a new advantageous crystal form of puerarin, puerarin-V, has been developed. However, the cardioprotective effects of puerarin-V on myocardial infarction (MI) heart failure are still unclear. In this research, we aim to evaluate the cardioprotective effects of puerarin-V on the isoproterenol (ISO)-induced MI mice and elucidate the underlying mechanisms. To induce MI in C57BL/6 mice, ISO was administered at 40 mg/kg subcutaneously every 12 h for three times in total. The mice were randomly divided into nine groups: (1) control; (2) ISO; (3) ISO + puerarin injection; (4–9) ISO + puerarin-V at different doses and timings. After treatment, cardiac function was evaluated by electrocardiogram (ECG), biochemical and histochemical analysis. In vitro inflammatory responses and apoptosis were evaluated in human coronary artery endothelial cells (HCAECs) challenged by lipopolysaccharide (LPS). LPS-induced PPAR-Υ/NF-κB and subsequently activation of cytokines were assessed by the western blot and real-time polymerase chain reaction (PCR). Administration of puerarin-V significantly inhibits the typical ST segment depression compared with that in MI mice. Further, puerarin-V treatment significantly improves ventricular wall infarction, decreases the incidence of mortality, and inhibits the levels of myocardial injury markers. Moreover, puerarin-V treatment reduces the inflammatory milieu in the heart of MI mice, thereby blocking the upregulation of proinflammatory cytokines (TNF-α, IL-1β and IL-6). The beneficial effects of puerarin-V might be associated with the normalization in gene expression of PPAR-Υ and PPAR-Υ/NF-κB /ΙκB-α/ΙΚΚα/β phosphorylation. In the in vitro experiment, treatment with puerarin-V (0.3, 1 and 3 μM) significantly reduces cell death and suppresses the inflammation cytokines expression. Likewise, puerarin-V exhibits similar mechanisms. The cardioprotective effects of puerarin-V treatment on MI mice in the pre + post-ISO group seem to be more prominent compared to those in the post-ISO group. Puerarin-V exerts cardioprotective effects against ISO-induced MI in mice, which may be related to the activation of PPAR-γ and the inhibition of NF-κB signaling in vivo and in vitro. Taken together, our research provides a new therapeutic option for the treatment of MI in clinic.

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Exosomal miR-25-3p from mesenchymal stem cells alleviates myocardial infarction by targeting pro-apoptotic proteins and EZH2

Cell Death and Disease ◽

10.1038/s41419-020-2545-6 ◽

2020 ◽

Vol 11 (5) ◽

Cited By ~ 1

Author(s):

Yi Peng ◽

Ji-Ling Zhao ◽

Zhi-Yong Peng ◽

Wei-Fang Xu ◽

Guo-Long Yu

Keyword(s):

Myocardial Infarction ◽

Inflammatory Responses ◽

Luciferase Assay ◽

Protective Effects ◽

Functional Studies ◽

Protein Levels ◽

Cardioprotective Effects ◽

Apoptotic Proteins

Abstract Mesenchymal stem cell (MSC) therapy is a promising approach against myocardial infarction (MI). Studies have demonstrated that MSCs can communicate with other cells by secreting exosomes. In the present study, we aimed to identify exosomal microRNAs that might contribute to MSC-mediated cardioprotective effects. Primary cardiomyocytes were deprived of oxygen and glucose to mimic MI in vitro. For the animal model of MI, the left anterior descending artery was ligated for 1 h, followed by reperfusion for 12 h. MSC-derived exosomes were used to treat primary cardiomyocytes or mice. Cardioprotection-related microRNAs were determined, followed by target gene identification and functional studies with quantitative PCR, western blotting, MTT assay, flow cytometry assay, chromatin immunoprecipitation and dual-luciferase assay. We found that MSC co-culture reduced OGD-induced cardiomyocyte apoptosis and inflammatory responses. Cardioprotection was also observed upon treatment with MSC-derived exosomes in vitro and in vivo. In line with this, exosome uptake led to a significant increase in miR-25-3p in cardiomyocytes. Depletion of miR-25-3p in MSCs abolished the protective effects of exosomes. Mechanistically, miR-25-3p directly targeted the pro-apoptotic genes FASL and PTEN and reduced their protein levels. Moreover, miR-25-3p decreased the levels of EZH2 and H3K27me3, leading to derepression of the cardioprotective gene eNOS as well as the anti-inflammatory gene SOCS3. Inhibition of EZH2 or overexpression of miR-25-3p in cardiomyocytes was sufficient to confer cardioprotective effects in vitro and in vivo. We concluded that exosomal miR-25-3p from MSCs alleviated MI by targeting pro-apoptotic proteins and EZH2.

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Targeting necroptosis as therapeutic potential in chronic myocardial infarction

Journal of Biomedical Science ◽

10.1186/s12929-021-00722-w ◽

2021 ◽

Vol 28 (1) ◽

Author(s):

Chanon Piamsiri ◽

Chayodom Maneechote ◽

Natthaphat Siri-Angkul ◽

Siriporn C. Chattipakorn ◽

Nipon Chattipakorn

Keyword(s):

Myocardial Infarction ◽

Therapeutic Potential ◽

Coronary Perfusion ◽

Beneficial Effects ◽

Cell Death Pathways ◽

Threatening Condition ◽

Underlying Mechanisms ◽

Novel Therapeutic Strategies

AbstractCardiovascular diseases (CVDs) are considered the predominant cause of morbidity and mortality globally. Of these, myocardial infarction (MI) is the most common cause of CVD mortality. MI is a life-threatening condition which occurs when coronary perfusion is interrupted leading to cardiomyocyte death. Subsequent to MI, consequences include adverse cardiac remodeling and cardiac dysfunction mainly contribute to the development of heart failure (HF). It has been shown that loss of functional cardiomyocytes in MI-induced HF are associated with several cell death pathways, in particular necroptosis. Although the entire mechanism underlying necroptosis in MI progression is still not widely recognized, some recent studies have reported beneficial effects of necroptosis inhibitors on cell viability and cardiac function in chronic MI models. Therefore, extensive investigation into the necroptosis signaling pathway is indicated for further study. This article comprehensively reviews the context of the underlying mechanisms of necroptosis in chronic MI-induced HF in in vitro, in vivo and clinical studies. These findings could inform ways of developing novel therapeutic strategies to improve the clinical outcomes in MI patients from this point forward.

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The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules

AJP Renal Physiology ◽

10.1152/ajprenal.00398.2012 ◽

2013 ◽

Vol 305 (2) ◽

pp. F143-F154 ◽

Cited By ~ 74

Author(s):

Harshini Mudaliar ◽

Carol Pollock ◽

Muralikrishna Gangadharan Komala ◽

Steven Chadban ◽

Huiling Wu ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Inflammatory Responses ◽

Proximal Tubules ◽

Peroxisome Proliferator ◽

Tlr2 Expression ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Diagnostic Threshold

Inflammatory responses are central to the pathogenesis of diabetic nephropathy. Toll-like receptors (TLRs) are ligand-activated membrane-bound receptors which induce inflammatory responses predominantly through the activation of NF-κB. TLR2 and 4 are present in proximal tubular cells and are activated by endogenous ligands upregulated in diabetic nephropathy, including high-mobility group box-1 (HMGB1) and fibronectin. Human proximal tubules were exposed to 5 mM (control), 11.2 mM (approximating the clinical diagnostic threshold for diabetes mellitus), and 30 mM (high) glucose for 72 h or 7 days. Cells were harvested for protein, mRNA, and nuclear extract to assess for TLR2, 4, and inflammatory markers. Glucose (11.2 mM) maximally increased TLR2 and 4 expression, HMGB1 release, and NF-κB activation with increased expression of cytokines. However, only TLR2 expression and subsequent NF-κB binding were sustained at 7 days. Recombinant HMGB1 induced NF-κB activation, which was prevented by both TLR2 silencing [small interfering (si)RNA] and TLR4 inhibition. Peroxisome proliferator-activated receptor-γ (PPAR-γ) transcription was reduced by exposure to 11.2 mM glucose with an increase observed at 30 mM glucose at 24 h. This may reflect a compensatory increase in PPAR-γ induced by exposure to 30 mM glucose, limiting the inflammatory response. Therefore, short-term moderate increases in glucose in vitro increase HMGB1, which mediates NF-κB activation through both TLR2 and 4. Furthermore, in vivo, streptozotocin-induced diabetic mice exhibited an increase in tubular TLR2 and HMGB1 expression. These results collectively suggest that TLR2 is likely to be the predominant long-term mediator of NF-κB activation in transducing inflammation in diabetic nephropathy.

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Canagliflozin Attenuates Lipotoxicity in Cardiomyocytes and Protects Diabetic Mouse Hearts by Targeting the mTOR/HIF-1α Pathway

10.21203/rs.3.rs-123774/v1 ◽

2020 ◽

Author(s):

Pengbo Sun ◽

Yipei Ding ◽

Jingyi Luo ◽

Jin Zhong ◽

Weidong Xie

Keyword(s):

Inflammatory Responses ◽

Mammalian Target Of Rapamycin ◽

Hypoxia Inducible Factor ◽

Diabetic Mouse ◽

Protective Effects ◽

Pharmacological Mechanism ◽

Beneficial Effects ◽

Mtor Phosphorylation

Abstract BackgroundLipotoxicity plays an important role in the development of diabetic cardiomyopathy and heart failure (HF). Canagliflozin (CAN), a marketed sodium-glucose co-transporter 2 inhibitor, has significant beneficial effects on HF. However, the potential pharmacological mechanism is still unknown.MethodsIn this study, we evaluated the protective effects and mechanism of CAN in the hearts of a C57BL/6J diabetic mouse model induced by a high-fat diet/streptozotocin (HFD/STZ) for 12 weeks in vivo and using HL-1 cells (a type of mouse cardiomyocyte line) induced by palmitic acid (PA) in vitro.ResultsCAN could significantly alleviate lipid accumulation and inflammatory responses in the hearts of the HFD/STZ-induced diabetic mice. Furthermore, CAN significantly attenuated the inflammatory injury induced by PA in the HL-1 cells. In addition, CAN bound to the mammalian target of rapamycin (mTOR) and significantly inhibited mTOR phosphorylation and hypoxia inducible factor-1α (HIF-1α) expression.ConclusionCAN attenuated lipotoxicity in cardiomyocytes and protected diabetic mouse hearts by targeting the mTOR/HIF-1α pathway.

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THE EFFICACY AND RELATIVE FIBRIN SELECTIVITY OF PROUROKINASE IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

10.1055/s-0038-1643573 ◽

1987 ◽

Author(s):

J Loscalzo

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Degradation Products ◽

Coronary Thrombosis ◽

Therapeutic Option ◽

Human Kidney ◽

Thrombolytic Agents ◽

Hemorrhagic Complications

The use of thrombolytic agents in acute myocardial infarction has gained widespread acceptance as an important early therapeutic option. Acute coronary thrombosis has been found in approximately 80% of patients with acute infarction and the use of standard thrombolytic agents opens these occluded vessels in most cases. Unfortunately, in many individuals standard agents also produce a systemic lytic state with its attendant hemorrhagic complications. Prourokinase (PUK) has been shown to be a relatively fibrin selective thrombolytic agent in vitro owing to its localized conversion to urokinase at the clot surface. Because of this desirable property, we studied the efficacy and selectivity of PUK in vivo in 19 patients with acute myocardial infarction. Each of these patients was documented by angiography to have a totally occluded infarct-related artery. Each patient was treated within six hours (range: 2 to 5.8 hours) of the onset of symptoms with 62.5 mg of PUK derived from the human kidney cell line, TCL598, infused intravenously over 90 minutes. Complete vessel patency was achieved in nine patients within 61 ± 19 minutes of the start of the infusion without apparent hemorrhagic complications. We evaluated the effect of PUK on fibrinogen, on nonspecific fibrinogen degradation products (FDP) the the fibrinogen/fibrin I peptide, Bβ 1-42, as well as on the specific fibrin degradation products, D-dimer (XDP) and the fibrin II peptide, Bβ 15-42. Values for these parameters measured before and at the end of the 90-minute infusion of PUK are given as the mean ± S.E.M.We conclude that PUK is an effective agent with which to achieve coronary thrombolysis and that at the doses used in this study, it aDDears to be relatively fibrin selective.

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UniPR1331: Small Eph/Ephrin Antagonist Beneficial in Intestinal Inflammation by Interfering with Type-B Signaling

Pharmaceuticals ◽

10.3390/ph14060502 ◽

2021 ◽

Vol 14 (6) ◽

pp. 502

Author(s):

Carmine Giorgio ◽

Marika Allodi ◽

Simone Palese ◽

Andrea Grandi ◽

Massimiliano Tognolini ◽

...

Keyword(s):

Intestinal Inflammation ◽

Inflammatory Responses ◽

Ischemia Reperfusion ◽

Drug Candidate ◽

Eph Receptors ◽

Beneficial Effects ◽

Bidirectional Signaling ◽

Novel Drug

Eph receptors, comprising A and B classes, interact with cell-bound ephrins generating bidirectional signaling. Although mainly related to carcinogenesis and organogenesis, the role of Eph/ephrin system in inflammation is growingly acknowledged. Recently, we showed that EphA/ephrin-A proteins can modulate the acute inflammatory responses induced by mesenteric ischemia/reperfusion, while beneficial effects were granted by EphB4, acting as EphB/ephrin-B antagonist, in a murine model of Crohn’s disease (CD). Accordingly, we now aim to evaluate the effects of UniPR1331, a pan-Eph/ephrin antagonist, in TNBS-induced colitis and to ascertain whether UniPR1331 effects can be attributed to A- or B-type signaling interference. The potential anti-inflammatory action of UniPR1331 was compared to those of the recombinant proteins EphA2, a purported EphA/ephrin-A antagonist, and of ephrin-A1-Fc and EphA2-Fc, supposedly activating forward and reverse EphA/ephrin-A signaling, in murine TNBS-induced colitis and in stimulated cultured mononuclear splenocytes. UniPR1331 antagonized the inflammatory responses both in vivo, mimicking EphB4 protection, and in vitro; EphA/ephrin-A proteins were inactive or only weakly effective. Our findings represent a further proof-of-concept that blockade of EphB/ephrin-B signaling is a promising pharmacological strategy for CD management and highlight UniPR1331 as a novel drug candidate, seemingly working through the modulation of immune responses.

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Immunotolerant Properties of Mesenchymal Stem Cells: Updated Review

Stem Cells International ◽

10.1155/2016/1859567 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 17

Author(s):

Whitney Faiella ◽

Rony Atoui

Keyword(s):

Myocardial Infarction ◽

Clinical Trial ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Therapeutic Option ◽

Clinical Use ◽

Healthy Donors

Stem cell transplantation is a potential therapeutic option to regenerate damaged myocardium and restore function after infarct. Current research is focused on the use of allogeneic mesenchymal stem cells (MSCs) due to their unique immunomodulatory characteristics and ability to be harvested from young and healthy donors. Both animal and human studies support the immunoprivileged state of MSCs and even demonstrate improvements in cardiac function after transplantation. This research continues to be a topic of interest, as advances will ultimately enable the clinical use of these universal cells for therapy after a myocardial infarction. Updatedin vitro,in vivo, and clinical trial studies are discussed in detail in the following review.

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Carbon Monoxide-Releasing Molecule-2 Ameliorates Particulate Matter-Induced Aorta Inflammation via Toll-Like Receptor/NADPH Oxidase/ROS/NF-κB/IL-6 Inhibition

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/2855042 ◽

2021 ◽

Vol 2021 ◽

pp. 1-22

Author(s):

Thi Thuy Tien Vo ◽

Chien-Yi Hsu ◽

Yinshen Wee ◽

Yuh-Lien Chen ◽

Hsin-Chung Cheng ◽

...

Keyword(s):

Carbon Monoxide ◽

Particulate Matter ◽

Nadph Oxidase ◽

Adhesion Molecule ◽

Inflammatory Responses ◽

Air Pollutant ◽

Matrix Metalloproteinase 2 ◽

Beneficial Effects

Particulate matter (PM), a major air pollutant, may be associated with adverse cardiovascular effects. Reactive oxygen species- (ROS-) dependent proinflammatory cytokine production, such as interleukin-6 (IL-6), is a possible underlying mechanism. Carbon monoxide- (CO-) releasing molecule-2 (CORM-2) which liberates exogenous CO can exert many beneficial effects, particularly anti-inflammation and antioxidant effects. The purpose of this study was to explore the protective effects and underpinning mechanisms of CORM-2 on PM-induced aorta inflammation. Here, human aortic vascular smooth muscle cells (HASMCs) were utilized as in vitro models for the assessment of signaling pathways behind CORM-2 activities against PM-induced inflammatory responses, including Toll-like receptors (TLRs), NADPH oxidase, ROS, nuclear factor-kappa B (NF-κB), and IL-6. The modulation of monocyte adherence and HASMC migration, that are two critical cellular events of inflammatory process, along with their regulators, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and matrix metalloproteinase-2 (MMP-2) and MMP-9, in response to PM by CORM-2, were further evaluated. Finally, mice experiments under different conditions were conducted for the in vivo evaluation of CORM-2 benefits on the expression of inflammatory molecules including IL-6, ICAM-1, VCAM-1, MMP-2, and MMP-9. Our results found that PM could induce aorta inflammation in vitro and in vivo, as evidenced by the increase of IL-6 expression that was regulated by the TLR2 and TLR4/NADPH oxidase/ROS/NF-κB signaling pathway, thereby promoting ICAM-1- and VCAM-1-dependent monocyte adhesion and MMP-2- and MMP-9-dependent HASMC migration. Importantly, our experimental models demonstrated that CORM-2-liberated CO effectively inhibited the whole identified PM-induced inflammatory cascade in HASMCs and tissues. In conclusion, CORM-2 treatment may elicit multiple beneficial effects on inflammatory responses of aorta due to PM exposure, thereby providing therapeutic value in the context of inflammatory diseases of the cardiovascular system.

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Statins Stimulate New Myocyte Formation After Myocardial Infarction by Activating Growth and Differentiation of the Endogenous Cardiac Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21217927 ◽

2020 ◽

Vol 21 (21) ◽

pp. 7927

Author(s):

Eleonora Cianflone ◽

Donato Cappetta ◽

Teresa Mancuso ◽

Jolanda Sabatino ◽

Fabiola Marino ◽

...

Keyword(s):

Myocardial Infarction ◽

Cell Biology ◽

Statin Treatment ◽

Border Zone ◽

Brdu Incorporation ◽

Akt Phosphorylation ◽

Beneficial Effects ◽

Reductase Inhibitors

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert pleiotropic effects on cardiac cell biology which are not yet fully understood. Here we tested whether statin treatment affects resident endogenous cardiac stem/progenitor cell (CSC) activation in vitro and in vivo after myocardial infarction (MI). Statins (Rosuvastatin, Simvastatin and Pravastatin) significantly increased CSC expansion in vitro as measured by both BrdU incorporation and cell growth curve. Additionally, statins increased CSC clonal expansion and cardiosphere formation. The effects of statins on CSC growth and differentiation depended on Akt phosphorylation. Twenty-eight days after myocardial infarction by permanent coronary ligation in rats, the number of endogenous CSCs in the infarct border zone was significantly increased by Rosuvastatin-treatment as compared to untreated controls. Additionally, commitment of the activated CSCs into the myogenic lineage (c-kitpos/Gata4pos CSCs) was increased by Rosuvastatin administration. Accordingly, Rosuvastatin fostered new cardiomyocyte formation after MI. Finally, Rosuvastatin treatment reversed the cardiomyogenic defects of CSCs in c-kit haploinsufficient mice, increasing new cardiomyocyte formation by endogenous CSCs in these mice after myocardial infarction. In summary, statins, by sustaining Akt activation, foster CSC growth and differentiation in vitro and in vivo. The activation and differentiation of the endogenous CSC pool and consequent new myocyte formation by statins improve myocardial remodeling after coronary occlusion in rodents. Similar effects might contribute to the beneficial effects of statins on human cardiovascular diseases.

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Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine

Science Translational Medicine ◽

10.1126/scitranslmed.aay1318 ◽

2020 ◽

Vol 12 (561) ◽

pp. eaay1318 ◽

Cited By ~ 1

Author(s):

Ling Gao ◽

Lu Wang ◽

Yuhua Wei ◽

Prasanna Krishnamurthy ◽

Gregory P. Walcott ◽

...

Keyword(s):

Myocardial Infarction ◽

Therapeutic Option ◽

Wall Stress ◽

Left Ventricular ◽

Cardiac Cells ◽

Left Ventricular Ejection ◽

Cell Group ◽

Ventricular Ejection Fraction

Cell therapy treatment of myocardial infarction (MI) is mediated, in part, by exosomes secreted from transplanted cells. Thus, we compared the efficacy of treatment with a mixture of cardiomyocytes (CMs; 10 million), endothelial cells (ECs; 5 million), and smooth muscle cells (SMCs; 5 million) derived from human induced pluripotent stem cells (hiPSCs), or with exosomes extracted from the three cell types, in pigs after MI. Female pigs received sham surgery; infarction without treatment (MI group); or infarction and treatment with hiPSC-CMs, hiPSC-ECs, and hiPSC-SMCs (MI + Cell group); with homogenized fragments from the same dose of cells administered to the MI + Cell group (MI + Fra group); or with exosomes (7.5 mg) extracted from a 2:1:1 mixture of hiPSC-CMs:hiPSC-ECs:hiPSC-SMCs (MI + Exo group). Cells and exosomes were injected into the injured myocardium. In vitro, exosomes promoted EC tube formation and microvessel sprouting from mouse aortic rings and protected hiPSC-CMs by reducing apoptosis, maintaining intracellular calcium homeostasis, and increasing adenosine 5′-triphosphate. In vivo, measurements of left ventricular ejection fraction, wall stress, myocardial bioenergetics, cardiac hypertrophy, scar size, cell apoptosis, and angiogenesis in the infarcted region were better in the MI + Cell, MI + Fra, and MI + Exo groups than in the MI group 4 weeks after infarction. The frequencies of arrhythmic events in animals from the MI, MI + Cell, and MI + Exo groups were similar. Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial recovery without increasing the frequency of arrhythmogenic complications and may provide an acellular therapeutic option for myocardial injury.

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