Prevents Cardiomyocyte Apoptosis Research Articles

Cyanidin prevents cardiomyocyte apoptosis in mice after myocardial infarction.

Myocardial infarction is a worldwide disease with high morbidity and mortality and a major cause of chronic heart failure, seriously affecting patients' quality of life. Natural medicine has been used to cure or prevent cardiovascular disease for decades. As a natural flavonoid, anthocyanidin has been used to treat many diseases due to its antioxidative, anti-inflammatory, and other properties. A mouse model (C57BL/6) weighing 30-40g was utilized to induce myocardial infarction by ligating the left anterior descending coronary artery. Cyanidin (30mg/kg) was administered orally to mice for four weeks. A variety of assessments were used to evaluate cardiac function. The gene expression was measured using RNAseq and Western blot. Histological changes in myocardial tissue were assessed using staining techniques, including Masson, Hematoxylin Eosin (HE), and transmission electron microscopy. Tunnel staining was implemented as a method to detect cellular apoptosis. For the quantification of B-type natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) in the serum, an enzyme-linked immunosorbent assay (ELISA) was employed. Furthermore, autodock simulation was executed in order to assess the interaction between cyanidin and a subset of genes. Cyanidin treatment inhibited myocardial cell apoptosis, improved cardiac function, and reduced serum concentrations of BNP and atrial natriuretic peptide ANP, as well as mitigated histological cardiac tissue damage. Cyanidin also inhibited the activity of matrix metalloproteinases (MMP2/9) and Fibronectin 1 (Fn1). Cyanidin improves heart function and reduces myocardial damage in mice after MI. Furthermore, cyanidin can prevent cardiomyocyte apoptosis. These effects are most likely caused by suppression of MMP9/2 and control of the Akt signaling pathway, suggesting an appropriate therapeutic target.

Alcohol Intake Provoked Cardiomyocyte Apoptosis Via Activating Calcium-Sensing Receptor and Increasing Endoplasmic Reticulum Stress and Cytosolic [Ca2+]i.

Cardiomyocyte apoptosis plays an important role in alcoholic cardiac injury. However, the association between calcium-sensing receptor (CaSR) and alcohol-induced cardiomyocyte apoptosis remain unclear. Therefore, we investigated the role and its moleculer mechanism of CaSR in rat cardiomyocyte apoptosis induced by alcohol. Alcohol-induced cardiomyocyte apoptosis in vivo and in vitro model of rats were applied in this study. The expression of CaSR, endoplasmic reticulum stress markers and apoptosis were tested by immunohistological staining, western blot, TUNEL and flow cytometry, respectively. [Ca2+]i were detected by confocal laser scanning microscopy. Compared with the control group, alcohol intake (AI) led to abnormal arrangements of cardiomyocytes and obvious increase of myocardial apoptosis. Moreover, AI also significantly upregulated protein expression of CaSR, GRP94, caspase-12 and CHOP. Alcohol induced apoptosis of cultured cardiomyocytes of rats in a dose-dependent way. Activation of CaSR markedly enhanced cardiomyocyte apoptosis and ERS induced by alcohol, ERS inducer also significantly increased cardiomyocyte apoptosis without activating CaSR. Furthermore, GdCl3 augmented alcohol-induced increase of [Ca2+]i in cardiomyocytes, which was attenuated by NPS2390 but not 4-PBA pre-treatment. Alcohol could induce cardiomyocyte apoptosis in rats in vivo and in vitro, which was mediated probably via activating CaSR, and then ERS and the increase of the cytosolic [Ca2+]i. This provides a potential target for preventing cardiomyocyte apoptosis and cardiomyopathy induced by alochol.

Nogo-A Mediated Endoplasmic Reticulum Stress During Myocardial Ischemic-Reperfusion Injury in Diabetic Rats.

Among the three isoforms encoded by neurite outgrowth inhibitor proteins has been intensely investigated as a central nervous system inhibitor. Although neurite outgrowth inhibitor protein-A (Nogo-A) expression is increased in plasma of patients who have experienced a coronary heart disease, its role in heart disease is not well elucidated. In this study, we discovered a significant increase in Nogo-A expression in diabetic myocardial ischemia reperfusion (MI/R) injury conditions. Accelerated Nogo-A and MI/R injury in diabetic rats was attenuated by tauroursodeoxycholic acid treatment and knockdown of Nogo-A per se is sufficient to decrease endoplasmic reticulum (ER) stress as well as prevents cardiomyocyte apoptosis. We hypothesized that decreased Nogo-A levels might reducing diabetic MI/R injury. Nogo-A interacted with C/EBP homologous protein, suggesting a role for Nogo-A in ER stress during diabetic MI/R. In conclusion, Nogo-A mediated ER stress plays a major role in diabetic MI/R injury, and pathologically altered Nogo-A expression mediates diabetic MI/R injury, suggesting Nogo-A as a novel target for the treatment of diabetic MI/R injury in clinical settings.

Extract of Platycodon grandiflorum Prevents Doxorubicin-induced Cardiotoxicity in Breast Cancer.

Doxorubicin (Dox) is a first-line chemotherapeutic agent applied in cancer treatment. Its long-term anticancer efficacy is restricted mainly due to its subsequent cardiotoxicity for patients. Platycodon grandiflorum (PG), an important traditional Chinese herb, has been reported to eliminate phlegm, relieve cough, and reduce inflammatory diseases. Previous clinical studies found that PG has cardioprotective effects for early breast cancer patients who received Dox-based chemotherapy. However, the cellular and molecular mechanisms underlying PG-mediated cardiotoxic rescue remain elusive. This study aimed to explore the protective role and potential molecular mechanisms of PG on Dox-induced cardiac dysfunction in a mouse model of breast cancer. PG significantly alleviated myocardial damage and prevented cardiomyocyte apoptosis induced by Dox. The expression levels of cytochrome C and cleaved caspase-3 significantly decreased, and the levels of Bcl-XL and B-cell lymphoma-2 (Bcl-2)/Bcl-2-associated X protein increased following PG treatment. Furthermore, PG remarkably enhanced the antimetastatic efficacy (versus the Dox group) by regulating the balance of matrix metalloproteinases/tissue inhibitors of metalloproteinases.

Agomir of miRNA-30d – a potential new therapeutic target for prevention of ischemic cardiomyopathy after myocardial infarction?

Abstract Background MicroRNA (miR)-30d is not only a valuable biomarker for assessing the extent of cardiac remodeling after myocardial infarction (MI), but also an important predictor of clinical outcome in heart failure. Overexpression of miRNA-30d appears to have a cardioprotective effect by preventing cardiomyocyte apoptosis as well as averting cardiac fibroblast proliferation via multiple molecular pathways. The aim of the present in vivo and in vitro study was to demonstrate whether an miR-30d can be a potential therapeutic target to reduce the risk of ischemic cardiomyopathy (iCMP) after MI. Methods First of all, miRNA profiling was performed by next generation sequencing (NGS) to assess differences in miRNA expression in ischemic vs. healthy myocardium in a rat model of MI using coronary artery ligation (ischemia/reperfusion injury, IR). MiR-30d was selected as the most promising target as it was significantly downregulated in ischemic myocardium and can be upregulated by cardioprotective agents. Therefore, an agomir of miR-30d was administered in the respective treatment group intraperitoneally, whereas non-functional, scrambled miRNA was administered in the control group. To analyze the ratio between phosphorylated p53 (pp53) and total p53, apoptosis was evaluated in human cardiomyocytes using a p53 and pp53 ELISA kit. To gain indirect insight into infarct healing, scratch assays were used to obtain information on cell migration in human umbilical vein endothelial cells (HUVEC) in vitro. Six weeks after the in vivo induction of acute MI/IR with consequential iCMP in a rat model, the extent of MI was evaluated by planimetry. Results The majority of miRNAs studied here showed significant up-regulation in the MI-induced heart tissue in comparison to the sham operated controls. In contrast, miRNA-30d was highly significantly reduced (p<0.001). Based on these investigations and the already repeatedly documented cardioprotective effect of miR-30d overexpression, an agomir was selected as a potential therapy target. Human cardiomyocytes under the influence of an agomir of miR-30d showed a decreased pp53/total p53 ratio (0.66±0.09 vs. 0.81±0.19) and thus a distinct tendency (p=0.055) for a reduction in apoptotic rate compared to the control group. In HUVECs, gap closure was significantly faster in the agomir treated cells 20h and 26h post-scratching (19.1% more than scrambled control after 20h; p=0.0028 and 18.7% more than scrambled control after 26h; p=0.0081). In the in vivo model, infarct size of left ventricle was significantly reduced by using the agomir (7.43±4.13% vs. 12.76±4.76%; p=0.0172). Conclusion Using an agomir of miR-30d underlines the cardioprotective effects of miR-30d in MIR/IR and could reduce the risk for iCMP development. Further investigations regarding its therapeutic potential in the human should be considered, as microRNA treatments are gaining more and more clinical applicability today. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Paracelsus Medical University, PMU-FFF

Sulforaphane inhibits angiotensin II-induced cardiomyocyte apoptosis by acetylation modification of Nrf2.

Oxidative stress is the central cause of angiotensin II (Ang II)-induced myocardial injury, and nuclear factor erythroid 2-related factor (Nrf2) is the core molecule of the anti-oxidant defense system. We have previously demonstrated that sulforaphane (SFN) can prevent Ang II-induced myocardial injury by activating Nrf2; however, the underlying molecular mechanism is still unclear. This study aimed to evaluate whether SFN prevents Ang II-induced cardiomyocyte apoptosis through acetylation modification of Nrf2. Wild-type and Nrf2 knockdown embryonic rat cardiomyocytes (H9C2) were exposed to Ang II to induce apoptosis, oxidative stress, and inflammatory responses. SFN treatment significantly reduced Ang II-induced cardiomyocyte apoptosis, inflammation and oxidative stress. Activation of Nrf2 played a critical role in preventing cardiomyocyte apoptosis. After Nrf2 was knockdown, the anti-inflammatory, antioxidant stress of SFN were eliminated. Furthermore, Nrf2 activation by SFN was closely related to the decreased activity of histone deacetylases (HDACs) and increased histone-3 (H3) acetylation levels in Nrf2 promoter region. These findings confirm that Nrf2 plays a key role in SFN preventing Ang II-induced cardiomyocyte apoptosis. SFN activates Nrf2 by inhibiting HDACs expression and activation.

CircRNA Samd4 induces cardiac repair after myocardial infarction by blocking mitochondria-derived ROS output

Reactive oxygen species (ROS) derived from oxygen-dependent mitochondrial metabolism are the essential drivers of cardiomyocyte (CM) cell-cycle arrest in adulthood. Mitochondria-localized circular RNAs (circRNAs) play important roles in regulating mitochondria-derived ROS production, but their functions in cardiac regeneration are still unknown. Herein, we investigated the functions and underlying mechanism of mitochondria-localized circSamd4 in cardiac regeneration. We found that circSamd4 was selectively expressed in fetal and neonatal CMs. The transcription factor Nrf2 controlled circSamd4 expression by binding to the promoter of circSamd4 host gene. CircSamd4 overexpression reduced while circSamd4 silenced increased mitochondrial oxidative stress and subsequent oxidative DNA damage. Moreover, circSamd4 overexpression induced CM proliferation and prevented CM apoptosis, which reduced the size of the fibrotic area and improved cardiac function after myocardial infarction (MI). Mechanistically, circSamd4 reduced oxidative stress generation and maintained mitochondrial dynamics by inducing the mitochondrial translocation of the Vcp protein, which downregulated Vdac1 expression and prevented the mitochondrial permeability transition pore (mPTP) from opening. Our findings suggest that circSamd4 is a novel therapeutic target for heart failure after MI.

An injectable mitochondria-targeted nanodrug loaded-hydrogel for restoring mitochondrial function and hierarchically attenuating oxidative stress to reduce myocardial ischemia-reperfusion injury

Timely reperfusion is the common treatment for myocardial infarction. However, ischemia-reperfusion (I/R) therapy can lead to oxidative stress and mitochondrial dysfunction that further aggravate myocardial injury, and no effective therapy is currently available for alleviating myocardial I/R injury. Herein, we engineer a mitochondria-targeted Szeto-Schiller (SS31) peptide modified-amphiphilic polymer (PTPS) that self-assembles into nanomicelles (PTPSCs) for loading cyclosporine A (CsA). The PTPSCs are then encapsulated into a pH/ROS dual responsive injectable hydrogel crosslinked with reversible imine and boronic ester bonds. The loaded PTPSCs are controllably delivered from the hydrogel matrix in response to the low pH and high ROS microenvironment of the I/R heart, thus realizing reconstruction of mitochondrial function and unprecedented hierarchical attenuation of oxidative stress. The boronic ester in the hydrogel consumes the ROS in cardiac microenvironment, and the mitochondria-targeted delivery of CsA is revealed to inhibit mitochondria-mediated apoptosis signaling pathway to prevent cardiomyocyte apoptosis, meanwhile attenuating the mitochondrial ROS output to reduce the level of cytosolic ROS. Additionally, SS31 can also serve as an antioxidant to consume ROS in the mitochondria. In rat model of myocardial I/R injury with administration of this injectable hydrogel, the targeted release of PTPSCs efficiently restores mitochondrial and cardiac function.

Levosimendan Postconditioning Attenuates Cardiomyocyte Apoptosis after Myocardial Infarction.

Background Levosimendan preconditioning has been shown to attenuate myocardial apoptosis in animal models. However, protective effects of levosimendan postconditioning against myocardial apoptosis following myocardial infarction (MI) have not been evaluated. Therefore, we investigated the effects of levosimendan postconditioning on myocardial apoptosis in MI rat models. Methods In an anoxia/reoxygenation (A/R) model, H9c2 cells were pretreated with or without levosimendan postconditioning after which their apoptosis rates were assessed by flow cytometry, RT-qPCR, and western blot analyses. Then, postconditioning was performed with or without levosimendan in MI rat models. Myocardiocyte apoptosis was evaluated by echocardiography, TTC staining, TUNEL staining, immunohistochemical staining, RT-qPCR, and western blot analysis. Results Levosimendan postconditioning inhibited H9c2 cell apoptosis in A/R models by elevating Bcl-2 while suppressing Caspase-3 and Bax at both mRNA and protein levels. Moreover, it improved cardiac functions and reduced the left ventricle infarction area in MI rat models. Compared to the MI control group, cardiomyocyte apoptosis rates in the levosimendan postconditioning group were low. The reduced cardiomyocyte apoptosis rates were associated with downregulation of Bax and Caspase-3 as well as with upregulation of Bcl-2 at mRNA and protein levels. Conclusions Levosimendan postconditioning of MI rat models protected against cardiomyocyte apoptosis, implying that it is a potential strategy for preventing cardiomyocyte apoptosis in the treatment of cardiac dysfunction following MI.

Bone morphogenetic protein 1.3 inhibition decreases scar formation and supports cardiomyocyte survival after myocardial infarction

Despite the high prevalence of ischemic heart diseases worldwide, no antibody-based treatment currently exists. Starting from the evidence that a specific isoform of the Bone Morphogenetic Protein 1 (BMP1.3) is particularly elevated in both patients and animal models of myocardial infarction, here we assess whether its inhibition by a specific monoclonal antibody reduces cardiac fibrosis. We find that this treatment reduces collagen deposition and cross-linking, paralleled by enhanced cardiomyocyte survival, both in vivo and in primary cultures of cardiac cells. Mechanistically, we show that the anti-BMP1.3 monoclonal antibody inhibits Transforming Growth Factor β pathway, thus reducing myofibroblast activation and inducing cardioprotection through BMP5. Collectively, these data support the therapeutic use of anti-BMP1.3 antibodies to prevent cardiomyocyte apoptosis, reduce collagen deposition and preserve cardiac function after ischemia.

NDP52 Protects Against Myocardial Infarction-Provoked Cardiac Anomalies Through Promoting Autophagosome-Lysosome Fusion via Recruiting TBK1 and RAB7.

Aims: Acute myocardial infarction (MI), caused by acute coronary artery obstruction, is a common cardiovascular event leading to mortality. Nuclear dot protein 52 (NDP52) is an essential selective autophagy adaptor, although its function in MI is still obscure. This study was designed to examine the function of NDP52 in MI and the associated mechanisms. Results: Our results revealed that MI challenge overtly impaired myocardial geometry and systolic function, along with cardiomyocyte apoptosis, myocardial interstitial fibrosis, and mitochondrial damage, and NDP52 nullified such devastating responses. Further studies showed that the blockade of mitochondrial clearance is related to MI-induced buildup of damaged mitochondria. Mechanistic approaches depicted that 7-day MI induced abnormal mitophagy flux, resulting in poor lysosomal clearance of injured mitochondria. NDP52 promoted mitophagy flux through the recruitment of Ras-associated protein RAB7 (RAB7) and TANK-binding kinase 1 (TBK1). On protein co-localization, TBK1 phosphorylated RAB7, in line with the finding that chloroquine or a TBK1 inhibitor reversed NDP52-dependent beneficial responses. Innovation: This study denoted a novel mechanism that NDP52 promotes cardioprotection against ischemic heart diseases through interaction with TBK1 and RAB7, leading to RAB7 phosphorylation, induction of mitophagy to clear ischemia-induced impaired mitochondria, thus preventing cardiomyocyte apoptosis in MI. Conclusion: Our results indicate that NDP52 promotes autophagic flux and clears damaged mitochondria to diminish reactive oxygen species and cell death in a TBK1/RAB7-dependent manner and thus limits MI-induced injury. Antioxid. Redox Signal. 36, 1119-1135.

Icarrin prevents cardiomyocyte apoptosis in spontaneously hypertensive rats by inhibiting endoplasmic reticulum stress pathways.

This study aimed to explore whether icarrin (ICA) can protect cardiomyocytes from hypertension-induced damage by inhibiting endoplasmic reticulum stress (ERS). Spontaneously hypertensive rats (SHRs) were orally administered water or ICA at 10, 20 and 40 mg/kg once daily for 12 weeks, and Wistar-Kyoto (WKY) rats were used as control. Changes in the growth and blood pressure of rats were assessed. Cardiac function was determined by ultrasound and the left ventricle mass was calculated. Myocardial tissue structure was assessed by haematoxylin and eosin staining, cardiomyocyte apoptosis was observed by TUNEL staining and the expression of ERS-related proteins was determined by western blotting. In the SHR group, blood pressure was significantly high, left ventricular function decreased and left ventricular mass index increased. Additionally, left ventricular cardiomyocyte hypertrophy, disordered myofilament arrangement and increased cardiomyocyte apoptosis were observed by histological staining. ERS-induced proteins associated with apoptosis, including GRP78, PERK, ATF-6, ATF-4, CHOP, DR5, Caspase 12, c-JUN and ASK-1 were found to be highly expressed. ICA treatment reduced blood pressure and regulated the expression of proteins induced by ERS. Cardiomyocyte apoptosis decreased and left ventricular function improved. ICA can inhibit ERS-induced apoptosis of cardiomyocytes and protect ventricular function in SHR.

Mangiferin prevents myocardial infarction-induced apoptosis and heart failure in mice by activating the Sirt1/FoxO3a pathway.

Myocardial infarction (MI) commonly leads to cardiomyocyte apoptosis and heart failure. Mangiferin is a natural glucosylxanthone extracted from mango fruits and leaves, which has anti‐apoptotic and anti‐inflammatory properties in experimental cardiovascular diseases. In the present study, we investigated the role and detailed mechanism of mangiferin in MI. We used ligation of the left anterior descending coronary artery to establish an MI model in vivo, and cardiomyocyte‐specific Sirt1 knockout mice were used to identify the mechanism of mangiferin. For in vitro studies, oxygen and glucose deprivation (OGD) was used to mimic ischaemia in H9c2 cardiomyocytes. In mice, mangiferin treatment increased Sirt1 expression after MI, significantly reduced the infarct area, and prevented MI‐induced apoptosis and heart failure. Mangiferin reduced OGD‐induced cellular apoptosis in H9c2 cells. Meanwhile, Sirt1 knockout/silencing abolished the protective effects of mangiferin. Further studies revealed that mangiferin increased FoxO3a deacetylation by up‐regulating Sirt1, thus preventing apoptosis, and adenovirus‐mediated constitutive acetylation of FoxO3a restricted the anti‐apoptotic effects of mangiferin in vivo and in vitro. Our results indicate that mangiferin prevents cardiomyocyte apoptosis and the subsequent heart failure by activating the Sirt1/FoxO3a pathway in MI, and suggest that mangiferin may have an interesting potential in following studies towards clinical evaluation.

MALAT1-mediated recruitment of the histone methyltransferase EZH2 to the microRNA-22 promoter leads to cardiomyocyte apoptosis in diabetic cardiomyopathy

Diabetic patients often have a heightened risk of cardiomyopathy, even in the absence of traditional risk factors such as hypertension and atherosclerotic coronary artery disease. Diabetic cardiomyopathy is characterized by a typical cardiomyopathy specific to diabetes, the pathogenesis of which has yet to be fully elucidated. As a well-documented oncogenic long noncoding RNA (lncRNA), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been implicated in a variety of pathological processes, including diabetic complications. This study aimed to evaluate the functional roles of MALAT1 in the pathogenesis of diabetic cardiomyopathy. Spontaneously diabetic (db/db) C57BL/Ks mice were employed to establish diabetic cardiomyopathy models in vivo and high glucose (HG)-cultured mouse cardiomyocytes for myocardial damage models in vitro. Mouse left ventricular volume and function were evaluated by echocardiography, while the myocyte cross-sectional area was calculated to evaluate the degree of myocardial hypertrophy. TUNEL staining and flow cytometric analysis were performed to evaluate myocardial damage and cardiomyocyte apoptosis. Silencing of MALAT1 was found to attenuate cardiac dysfunction and inhibit cardiomyocyte apoptosis in db/db mice and HG-cultured mouse cardiomyocytes. MALAT1 recruited the histone methyltransferase EZH2 to the miR-22 promoter region and inhibited its expression. EZH2 induced an increased in the expression of ATP-binding cassette transporter A1 (ABCA1), which was identified to be a target gene of miR-22. Silencing of EZH2 was found to improve cardiac function and prevent cardiomyocyte apoptosis in db/db mice and HG-cultured mouse cardiomyocytes in the presence of MALAT1, suggesting that MALAT1 mediated myocardial damage by recruiting EZH2 to the miR-22 promoter. Taken together, this study's findings provide evidence confirming our hypothesis, suggesting the involvement of MALAT1 in the processes of cardiac function and cardiomyocyte apoptosis via the EZH2/miR-22/ABCA1 signaling cascade, which has potential therapeutic implications for the understanding of diabetic cardiomyopathy.

Crosstalk between cardiomyocytes and noncardiomyocytes is essential to prevent cardiomyocyte apoptosis induced by proteasome inhibition

Heart is a multi-cellular organ made up of various cell types interacting with each other. Cardiomyocytes may benefit or suffer from crosstalk with noncardiomyocytes in response to diverse kinds of cardiac stresses. Proteasome dysfunction is a common cardiac stress which causes cardiac proteotoxicity and contributes to cardiac diseases such as heart failure and myocardial infarction. The role of crosstalk between cardiomyocytes and noncardiomyocytes in defense of cardiac proteotoxicity remains unknown. Here, we report a cardiomyocyte-specific survival upon proteasome inhibition in a heterogeneous culture consisting of cardiomyocytes and other three major cardiac cell types. Conversely, cardiomyocyte apoptosis is remarkably induced by proteasome inhibition in a homogeneous culture consisting of a majority of cardiomyocytes, demonstrating an indispensable role of noncardiomyocytes in the prevention of cardiomyocyte apoptosis resulting from proteasome inhibition. We further show that cardiomyocytes express brain natriuretic peptide (BNP) as an extracellular molecule in response to proteasome inhibition. Blockade of BNP receptor on noncardiomyocytes significantly exacerbated the cardiomyocyte apoptosis, indicating a paracrine function of cardiomyocyte-released extracellular BNP in activation of a protective feedback from noncardiomyocytes. Finally, we demonstrate that proteasome inhibition-activated transcriptional up-regulation of BNP in cardiomyocytes was associated with the dissociation of repressor element 1 silencing transcription factor (REST)/ histone deacetylase 1 (HDAC1) repressor complex from BNP gene promoter. Consistently, the induction of BNP could be further augmented by the treatment of HDAC inhibitors. We conclude that the crosstalk between cardiomyocytes and noncardiomyocytes plays a crucial role in the protection of cardiomyocytes from proteotoxicity stress, and identify cardiomyocyte-released BNP as a novel paracrine signaling molecule mediating this crosstalk. These findings provide new insights into the key regulators and cardioprotective mechanism in proteasome dysfunction-related cardiac diseases.

Treatment with 17β‐estradiol protects donor heart against brain death effects in female rat

The viability of donor organs is reduced by hemodynamic and immunologic alterations caused by brain death (BD). Female rats show higher heart inflammation associated with the reduction in female sex hormones after BD. This study investigated the effect of 17β-estradiol (E2) on BD-induced cardiac damage in female rats. Groups of female Wistar rats were assigned: Sham-operation (Sham), brain death (BD), treatment with E2 (50μg/ml, 2ml/h) 3h after BD (E2-T3), or immediately after BD confirmation (E2-T0). White blood cell (WBC) count was analyzed; cytokines and troponin-I were quantified. Heart histopathological changes and expression of endothelial nitric oxide synthase, endothelin-1, intercellular adhesion molecule-1, BCL-2, and caspase-3 were evaluated. Cardiac function was continuously assessed for 6h by left ventricular pressure-volume loop analysis. E2 decreased the BD-induced median serum concentration of troponin-I (BD:864.2 vs. E2-T0:401.4; P=0.009), increased BCL-2 (BD:0.086 vs. E2-T0:0.158; P=0.0278) and eNOS median expression in the cardiac tissue (BD:0.001 vs. E2-T0:0.03 and E2-T3:0.0175; P<0.0001), and decreased caspase-3 (BD:0.025 vs. E2-T0:0.006 and E2-T3:0.019; P=0.006), WBC counts, leukocyte infiltration, and hemorrhage. 17β-estradiol treatment was effective in reducing cardiac tissue damage in brain-dead female rats owing to its ability to reduce leukocyte infiltration and prevent cardiomyocyte apoptosis.

Taurine prevents cardiomyocyte apoptosis by inhibiting the calpain-1/cytochrome c pathway during RVH in broilers

The calpain-1-activated apoptotic pathway plays a key role in right ventricular hypertrophy (RVH). Taurine has been shown to attenuate apoptosis by inhibiting calpain activity. This experiment aimed to determine whether taurine could prevent RVH by inhibiting the calpain-1/cytochrome c apoptotic pathway. The broilers were given 1% taurine dissolved in drinking water and were raised at 10°C ~ 12°C from day 21 to day 42. At 21 d, 28 d, 35 d and 42 d, the right ventricular (RV) tissues were collected. Increased RVH index, angiotensin II, norepinephrine and atrial natriuretic peptide mRNA expression were reduced by taurine in the broiler RVs. Taurine obviously inhibited cardiomyocyte apoptosis via maintaining the mitochondrial membrane potential and decreased the activation of caspase-9 and caspase-3 in the broiler RVs. The antioxidant assay demonstrated that taurine enhanced the activities of superoxide dismutase, total antioxidant capacity and glutathione peroxidase and the glutathione/glutathione disulfide ratio. Western blot results revealed that taurine also downregulated the expression of calpain-1 and cytosolic cytochrome c while upregulating the expression of Bcl-2/Bax and mitochondrial cytochrome c in broiler cardiomyocytes during RVH. In summary, we found that taurine could enhance cardiomyocyte antioxidant ability and further prevented cardiomyocyte apoptosis by inhibiting the calpain-1/cytochrome c pathway during RVH in broilers.

Macrophage migration inhibitory factor rejuvenates aged human mesenchymal stem cells and improves myocardial repair.

The beneficial functions of mesenchymal stem cells (MSCs) decline with age, limiting their therapeutic efficacy for myocardial infarction (MI). Macrophage migration inhibitory factor (MIF) promotes cell proliferation and survival. We investigated whether MIF overexpression could rejuvenate aged MSCs and increase their therapeutic efficacy in MI. Young and aged MSCs were isolated from the bone marrow of young and aged donors. Young MSCs, aged MSCs, and MIF-overexpressing aged MSCs were transplanted into the peri-infarct region in a rat MI model. Aged MSCs exhibited a lower proliferative capacity, lower MIF level, greater cell size, greater senescence-associated-β-galactosidase activity, and weaker paracrine effects than young MSCs. Knocking down MIF in young MSCs induced cellular senescence, whereas overexpressing MIF in aged MSCs reduced cellular senescence. MIF rejuvenated aged MSCs by activating autophagy, an effect largely reversed by the autophagy inhibitor 3-methyladenine. MIF-overexpressing aged MSCs induced angiogenesis and prevented cardiomyocyte apoptosis to a greater extent than aged MSCs, and had improved heart function and cell survival more effectively than aged MSCs four weeks after MI. Thus, MIF rejuvenated aged MSCs by activating autophagy and enhanced their therapeutic efficacy in MI, suggesting a novel MSC-based therapeutic strategy for cardiovascular diseases in the aged population.

Therapeutic effects of erythropoietin expressed in mesenchymal stem cells for dilated cardiomyopathy in rat

Dilated cardiomyopathy (DCM) is considered as the final common response of myocardium to diverse genetic and environmental insults and characterized mainly by left ventricular systolic dysfunction. The current therapies for the treatment of DCM are costly high and outcomes are often unsatisfactory. To date, mesenchymal stem cells (MSCs) have been thought to be an ideal stem cell to repair damaged myocardium but was still within relatively small scales and few cases have been conducted in clinical trials. The use of erythropoietin (EPO), a growth factor produced in the kidneys have been found prevent cardiomyocyte apoptosis. This study was aimed to transplant MSCs into DCM rat bone marrow to express EPO in vivo and investigate the regulation of EPO on cell signaling pathways after transfection. The results found that transplantation of MSCs carrying EPO could significantly relief the cardiac dysfunctions of the DCM rat. This underylying mechanism involved with inhibiting p–NF–κB and p-P38, regulateing and promoting the anti-inflammatory balance, thereby alleviating tissue injury in DCM rats and exhibiting a protective role. Meanwhile, the MSCs + EPO treatment in DCM rat also activated the p-Akt pathway and thus protecting the myocardium from apoptosis in DCM rats. The study revealed an potential therapeutic effect of MSCs and EPO in clinical and provided a molecular mechanism of action for treating DCM.

Exosomes from adipose-derived mesenchymal stem cells prevent cardiomyocyte apoptosis induced by oxidative stress

Exosomes from bone marrow stem cells or cardiac progenitor cells can reduce apoptosis in myocardial cells after ischemia and reperfusion injury. However, there is little known about the effects of exosomes from adipose-derived stem cells (ADSCs), which are more abundant and have a lower risk of side effects. The aim of this study was to characterize exosomes from ADSCs and evaluate their cardioprotective actions against ischemia reperfusion injury. The exosomes were isolated from ADSCs and analyzed by protein marker expression, transmission electron microscopy, and nanoparticle tracking analysis. The ADSC-exosomes were then used for ex vivo investigation of the cardioprotective effects on cardiomyocytes after exposure to oxidative stress. Exosomes from ADSCs exhibited a diameter of 150 nm and expressed the marker proteins, CD9 and CD29. ADSC-exosomes had no effect on proliferation of untreated cardiomyocytes. In contrast, ADSC-derived exosomes reduced apoptosis in myocardial cells subjected to oxidative stress. This study confirms that exosomes originating from ADSCs can protect cardiomyocytes from oxidative stress.