Oxidative stress and cardiomyocyte apoptosis play critical roles in doxorubicin (DOX)-induced cardiotoxicity. Previous studies indicated that fibronectin type III domain-containing 5 (FNDC5) and its ...cleaved form, irisin, could preserve mitochondrial function and attenuate oxidative damage as well as cell apoptosis, however, its role in DOX-induced cardiotoxicity remains unknown. Our present study aimed to investigate the role and underlying mechanism of FNDC5 on oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity. Cardiomyocyte-specific FNDC5 overexpression was achieved using an adeno-associated virus system, and then the mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg) to generate DOX-induced cardiotoxicity. Herein, we found that FNDC5 expression was downregulated in DOX-treated murine hearts and cardiomyocytes. Fndc5 deficiency resulted in increased oxidative damage and apoptosis in H9C2 cells under basal conditions, imitating the phenotype of DOX-induced cardiomyopathy in vitro, conversely, FNDC5 overexpression or irisin treatment alleviated DOX-induced oxidative stress and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, we identified that FNDC5/Irisin activated AKT/mTOR signaling and decreased DOX-induced cardiomyocyte apoptosis, and moreover, we provided direct evidence that the anti-oxidant effect of FNDC5/Irisin was mediated by the AKT/GSK3β/FYN/Nrf2 axis in an mTOR-independent manner. And we also demonstrated that heat shock protein 20 was responsible for the activation of AKT caused by FNDC5/Irisin. In line with the data in acute model, we also found that FNDC5/Irisin exerted beneficial effects in chronic model of DOX-induced cardiotoxicity (5 mg/kg, i.p., once a week for three times, the total cumulative dose is 15 mg/kg) in mice. Based on these findings, we supposed that FNDC5/Irisin was a potential therapeutic agent against DOX-induced cardiotoxicity.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The poor prognosis of patients with acute myocardial infarction is partially attributed to a large number of cardiomyocyte apoptosis, necrosis, limited cardiac healing and angiogenesis, and cardiac ...dysfunction. Immune cells dysfunction leads to nonhealing or poor healing of wounds after acute myocardial infarction. Toll-like receptor 9 (TLR9) as an essential part of the innate immune system plays a vital role in regulating cardiomyocyte survival and wound healing. During hypoxia, High Mobility Group Box 1 (HMGB1), as the typical damage-associated molecular patterns (DAMPs) or alarmin, is rapidly released extracellularly and translocates from the nucleus to bind with cytoplasmic TLR9. However, the mechanism by which TLR9 interacts with HMGB1 and regulates myocardial damage remains unclear. Our current study found that the survival rate of TLR9KO mice with a higher rate of cardiac rupture was significantly lower than that in WT mice after 28 days post-operation. The effect of TLR9 knockout on insufficient wound healing in experimental MI was caused by a diminished number of myofibroblast and defective matrix synthetic capability. Moreover, the increased myocardial apoptotic cells and decreased angiogenic capacity were found in TLR9 knockout mice after MI. The results showed contrary in Recombinant Human High Mobility Group Box 1 (rhHMGB1) treated WT mice and similarity after applying rhHMGB1 in TLR9KO mice. This study demonstrates that TLR9 is essential for the repair of infarcted myocardium and interaction of HMGB1 and TLR9 is involved in the survival of myocardial cells, wound healing, and angiogenesis after myocardial infarction.
Aging is an important risk factor for cardiovascular diseases, and aging‐related cardiac dysfunction serves as a major determinant of morbidity and mortality in elderly populations. Our previous ...study has identified fibronectin type III domain‐containing 5 (FNDC5) and its cleaved form, irisin, as the cardioprotectant against doxorubicin‐induced cardiomyopathy. Herein, aging or matched young mice were overexpressed with FNDC5 by adeno‐associated virus serotype 9 (AAV9) vectors, or subcutaneously infused with irisin to uncover the role of FNDC5 in aging‐related cardiac dysfunction. To verify the involvement of nucleotide‐binding oligomerization domain‐like receptor with a pyrin domain 3 (NLRP3) and AMP‐activated protein kinase α (AMPKα), Nlrp3 or Ampkα2 global knockout mice were used. Besides, young mice were injected with AAV9‐FNDC5 and maintained for 12 months to determine the preventive effect of FNDC5. Moreover, neonatal rat cardiomyocytes were stimulated with tumor necrosis factor‐α (TNF‐α) to examine the role of FNDC5 in vitro. We found that FNDC5 was downregulated in aging hearts. Cardiac‐specific overexpression of FNDC5 or irisin infusion significantly suppressed NLRP3 inflammasome and cardiac inflammation, thereby attenuating aging‐related cardiac remodeling and dysfunction. In addition, irisin treatment also inhibited cellular senescence in TNF‐α‐stimulated cardiomyocytes in vitro. Mechanistically, FNDC5 activated AMPKα through blocking the lysosomal degradation of glucagon‐like peptide‐1 receptor. More importantly, FNDC5 gene transfer in early life could delay the onset of cardiac dysfunction during aging process. We prove that FNDC5 improves aging‐related cardiac dysfunction by activating AMPKα, and it might be a promising therapeutic target to support cardiovascular health in elderly populations.
FNDC5 is downregulated in aging hearts, and cardiac‐specific overexpression of FNDC5 or irisin infusion attenuates aging‐related inflammation, cardiac remodeling, and dysfunction. Mechanistically, FNDC5 activates AMPKα through blocking the lysosomal degradation of GLP‐1R.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Aim
The Hengduan Mountains (HDM) of southwest China is a biodiversity hotspot and harbours one of the world's richest temperate floras. However, the origin and evolution of its biota remain largely ...unresolved. Here we explore the impact of mountain uplift on the diversification process of biodiversity in this hotspot using alpine bamboos.
Location
The HDM region, southwest China.
Taxon
Alpine bamboos.
Methods
We used ddRAD‐seq data from the most complete sampling of alpine bamboos undertaken to date (79% of the species diversity), to investigate their evolutionary history. The ancestral area of these bamboos was reconstructed using a time‐calibrated phylogeny in BioGeoBEARS and diversification rates were inferred using BAMM analyses. In addition, the impact of mountain uplift on the divergence of alpine bamboos was evaluated using trait‐dependent models of diversification.
Results
The alpine bamboos were strongly supported as monophyletic, and the relationships within them were robustly resolved. Fargesia was found to be polyphyletic and Yushania was resolved as monophyletic. Alpine bamboos originated outside the HDM region during the late Miocene, and spread to this region in the Pliocene, undergoing a significant acceleration in net diversification, which is temporally congruent with the orogeny. The speciation rate increased with altitude and a high diversification rate, estimated to be 0.75 species per million years, was detected for alpine bamboos distributed in high elevations.
Main Conclusions
Our study demonstrates that heterogeneous mountain habitats and geographical isolation of alpine bamboos, which have limited dispersal ability, are important drivers for their rapid diversification. This study also highlights the power of complementary analyses in revealing the link between species diversification and past geological changes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A roughness scaling behaviour is tested by performing the direct numerical simulation (DNS) of a turbulent channel flow over three-dimensional sinusoidal rough walls. By systematically varying the ...roughness height ${{k}^{+}}$ and the roughness steepness S, the results for three groups of cases are considered and compared with those for flat-wall turbulence. The results show that the mean velocity and Reynolds stresses are highly dependent on both ${{k}^{+}}$ and S. To describe these specific relationships, we define a coupling scale ${{k}^{+}} S$. With this coupling scale, all the simulated data for the roughness function (${\rm \Delta} {{U}^{+}}$), the ratio of the pressure drag to the total wall resistance (${{\gamma }_{p}}$), the normalized bulk mean velocity ($U_{b}^{+}$) and the peak of the streamwise turbulent velocity fluctuations ($\overline {u_{p}^{\prime +}}$) collapse onto single curves, which shows that there is a strong direct correlation between them, i.e. ${\rm \Delta} U^{+}, \gamma _{p}, U_{b}^{+}, \overline {u_{p}^{\prime +}} \propto f(k^{+} S)$. Furthermore, a model for the prediction of wall resistance based on the roughness function can be established by defining a drag increasing ratio (DI). Accordingly, the wall resistance coefficient ${{C}_{f}}$ can be estimated directly from ${{k}^{+}}S$ of a given rough surface. These results suggest that this coupling scale provides a useful alternative to the equivalent sand grain roughness ${{k}_{s}}$.
Meteorin-like (METRNL) protein is a newly identified myokine that functions to modulate energy expenditure and inflammation in adipose tissue. Herein, we aim to investigate the potential role and ...molecular basis of METRNL in doxorubicin (DOX)-induced cardiotoxicity. METRNL was found to be abundantly expressed in cardiac muscle under physiological conditions that was decreased upon DOX exposure. Cardiac-specific overexpression of METRNL by adeno-associated virus serotype 9 markedly improved oxidative stress, apoptosis, cardiac dysfunction and survival status in DOX-treated mice. Conversely, knocking down endogenous METRNL by an intramyocardial injection of adenovirus exacerbated DOX-induced cardiotoxicity and death. Meanwhile, METRNL overexpression attenuated, while METRNL silence promoted oxidative damage and apoptosis in DOX-treated H9C2 cells. Systemic METRNL depletion by a neutralizing antibody aggravated DOX-related cardiac injury and dysfunction in vivo, which were notably alleviated by METRNL overexpression within the cardiomyocytes. Besides, we detected robust METRNL secretion from isolated rodent hearts and cardiomyocytes, but to a less extent in those with DOX treatment. And the beneficial effects of METRNL in H9C2 cells disappeared after the incubation with a METRNL neutralizing antibody. Mechanistically, METRNL activated SIRT1 via the cAMP/PKA pathway, and its antioxidant and antiapoptotic capacities were blocked by SIRT1 deficiency. More importantly, METRNL did not affect the tumor-killing action of DOX in 4T1 breast cancer cells and tumor-bearing mice. Collectively, cardiac-derived METRNL activates SIRT1 via cAMP/PKA signaling axis in an autocrine manner, which ultimately improves DOX-elicited oxidative stress, apoptosis and cardiac dysfunction. Targeting METRNL may provide a novel therapeutic strategy for the prevention of DOX-associated cardiotoxicity.
Cardiac-derived METRNL activates SIRT1 via cAMP/PKA signaling axis in an autocrine manner, which ultimately improves DOX-elicited oxidative stress, apoptosis and cardiac dysfunction.DOX, doxorubicin; M, METRNL; ROS, reactive oxygen species; ATP, adenosine triphosphate; PKA, protein kinase A; CREB, cAMP responsive element binding protein; DBC1, deleted in breast cancer 1; SIRT1, silent information regulator 1; PGC1α, peroxisome proliferator-activated receptor γ coactivator 1α; FoxO; forkhead box O. Display omitted
•METRNL is abundant in the heart, yet decreased upon DOX treatment.•METRNL overexpression improves, while METRNL deficiency exacerbates DOX-induced cardiotoxicity in vivo and in vitro.•METRNL activates SIRT1 via cAMP/PKA signaling axis in an autocrine manner.•METRNL does not affect the tumor-killing action of DOX in cancer cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Inflammation and myocytes apoptosis play critical roles in the development of doxorubicin (DOX)-induced cardiotoxicity. Our previous study found that C1q/tumour necrosis factor-related protein-3 ...(CTRP3) could inhibit cardiac inflammation and apoptosis of myocytes but its role in DOX-induced heart injury remains largely unknown. Our study aimed to investigate whether CTRP3 protected against DOX-induced heart injury and the underlying mechanism.
We overexpressed CTRP3 in the hearts using an adeno-associated virus system. The mice were subjected to a single intraperitoneal injection of DOX (15mg/kg) to induce short-term model for cardiomyopathy. The morphological examination and biochemical analysis were used to evaluate the effects of CTRP3. H9C2 cells were used to verify the protective role of CTRP3 in vitro.
Myocardial CTRP3 protein levels were reduced in DOX-treated mice. Cardiac specific-overexpression of CTRP3 preserved heart dysfunction, and attenuated cardiac inflammation and cell loss induced by DOX in vivo and in vitro. CTRP3 could activate silent information regulator 1 (Sirt1) in vivo and in vitro. Moreover, specific inhibitor of Sirt1 and the silence of Sirt1 could abolish the protective effects of CTRP3 against DOX-induced inflammation and apoptosis.
CTRP3 protected against DOX-induced heart injury via activation of Sirt1. CTRP3 has therapeutic potential for the treatment of DOX cardiotoxicity.
•CTRP3 attenuated doxorubicin (DOX)-induced cardiac dysfunction, inflammation and cell death.•CTRP3 could activate Sirt1 in vivo and in vitro.•The deficiency of Sirt1 blocked the protective effects of CTRP3 in DOX-induced heart injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Pathological cardiac fibrosis is a common feature in multiple cardiovascular diseases that contributes to the occurrence of heart failure and life-threatening arrhythmias. Our previous study ...demonstrated that matrine could attenuate doxorubicin-induced oxidative stress and cardiomyocyte apoptosis. In this study, we investigated the effect of matrine on cardiac fibrosis. Mice received aortic banding (AB) operation or continuous injection of isoprenaline (ISO) to generate pathological cardiac fibrosis and then were exposed to matrine lavage (200 mg·kg
·d
) or an equal volume of vehicle as the control. We found that matrine lavage significantly attenuated AB or ISO-induced fibrotic remodeling and cardiac dysfunction. We also showed that matrine (200 μmol/L) significantly inhibited the proliferation, migration, collagen production, and phenotypic transdifferentiation of cardiac fibroblasts. Mechanistically, matrine suppressed p38 activation in vivo and in vitro, and overexpression of constitutively active p38 completely abolished the protective effects of matrine. We also demonstrated that ribosomal protein S5 (RPS5) upregulation was responsible for matrine-mediated inhibition on p38 and fibrogenesis. More importantly, matrine was capable of ameliorating preexisting cardiac fibrosis in mice. In conclusion, matrine treatment attenuates cardiac fibrosis by regulating RPS5/p38 signaling in mice, and it might be a promising therapeutic agent for treating pathological cardiac fibrosis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Proteasomal activity is compromised in diabetic hearts that contributes to proteotoxic stresses and cardiac dysfunction. Osteocrin (OSTN) acts as a novel exercise-responsive myokine and is implicated ...in various cardiac diseases. Herein, we aim to investigate the role and underlying molecular basis of OSTN in diabetic cardiomyopathy (DCM). Mice received a single intravenous injection of the cardiotrophic adeno-associated virus serotype 9 to overexpress OSTN in the heart and then were exposed to intraperitoneal injections of streptozotocin (STZ, 50 mg/kg) for consecutive 5 days to generate diabetic models. Neonatal rat cardiomyocytes were isolated and stimulated with high glucose to verify the role of OSTN in vitro. OSTN expression was reduced by protein kinase B/forkhead box O1 dephosphorylation in diabetic hearts, while its overexpression significantly attenuated cardiac injury and dysfunction in mice with STZ treatment. Besides, OSTN incubation prevented, whereas OSTN silence aggravated cardiomyocyte apoptosis and injury upon hyperglycemic stimulation in vitro. Mechanistically, OSTN treatment restored protein kinase G (PKG)-dependent proteasomal function, and PKG or proteasome inhibition abrogated the protective effects of OSTN in vivo and in vitro. Furthermore, OSTN replenishment was sufficient to prevent the progression of pre-established DCM and had synergistic cardioprotection with sildenafil. OSTN protects against DCM via restoring PKG-dependent proteasomal activity and it is a promising therapeutic target to treat DCM.
Cardiac fibrosis is defined as the imbalance of extracellular matrix (ECM) production and degradation, thus contributing to cardiac dysfunction in many cardiac pathophysiologic conditions. This ...review discusses specific markers and origin of cardiac fibroblasts (CFs), and the underlying mechanism involved in the development of cardiac fibrosis. Currently, there are no CFs-specific molecular markers. Most studies use co-labelling with panels of antibodies that can recognize CFs. Origin of fibroblasts is heterogeneous. After fibrotic stimuli, the levels of myocardial pro-fibrotic growth factors and cytokines are increased. These pro-fibrotic growth factors and cytokines bind to its receptors and then trigger the activation of signaling pathway and transcriptional factors via Smad-dependent or Smad independent-manners. These fibrosis-related transcriptional factors regulate gene expression that are involved in the fibrosis to amplify the fibrotic response. Understanding the mechanisms responsible for initiation, progression, and amplification of cardiac fibrosis are of great clinical significance to find drugs that can prevent the progression of cardiac fibrosis.
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