Diabetic cardiomyopathy (DCM) is a chronic complication of diabetes mellitus, characterized by abnormalities of myocardial structure and function. Researches on the models of type 1 and type 2 ...diabetes mellitus as well as the application of genetic engineering technology help in understanding the molecular mechanism of DCM. DCM has multiple hallmarks, including hyperglycemia, insulin resistance, increased free radical production, lipid peroxidation, mitochondrial dysfunction, endothelial dysfunction, and cell death. Essentially, cell death is considered to be the terminal pathway of cardiomyocytes during DCM. Morphologically, cell death can be classified into four different forms: apoptosis, autophagy, necrosis, and entosis. Apoptosis, as type I cell death, is the fastest form of cell death and mainly occurs depending on the caspase proteolytic cascade. Autophagy, as type II cell death, is a degradation process to remove damaged proteins, dysfunctional organelles and commences by the formation of autophagosome. Necrosis is type III cell death, which contains a great diversity of cell death processes, such as necroptosis and pyroptosis. Entosis is type IV cell death, displaying "cell-in-cell" cytological features and requires the engulfing cells to execute. There are also some other types of cell death such as ferroptosis, parthanatos, netotic cell death, lysosomal dependent cell death, alkaliptosis or oxeiptosis, which are possibly involved in DCM. Drugs or compounds targeting the signals involved in cell death have been used in clinics or experiments to treat DCM. This review briefly summarizes the mechanisms and implications of cell death in DCM, which is beneficial to improve the understanding of cell death in DCM and may propose novel and ideal strategies in future.
Hydrogen sulfide (H2S) has traditionally been viewed as a highly toxic gas; however, recent studies have implicated H2S as a third member of the gasotransmitter family, exhibiting properties similar ...to NO and carbon monoxide. Accumulating evidence has suggested that H2S influences a wide range of physiological and pathological processes, among which blood vessel relaxation, cardioprotection and atherosclerosis have been particularly studied. In the cardiovascular system, H2S production is predominantly catalyzed by cystathionine γ‐lyase (CSE). Decreased endogenous H2S levels have been found in hypertensive patients and animals, and CSE−/− mice develop hypertension with age, suggesting that a deficiency in H2S contributes importantly to BP regulation. H2S supplementation attenuates hypertension in different hypertensive animal models. The mechanism by which H2S was originally proposed to attenuate hypertension was by virtue of its action on vascular tone, which may be related to effects on different ion channels. Both H2S and NO cause vasodilatation and there is cross‐talk between these two molecules to regulate BP. Suppression of oxidative stress may also contribute to antihypertensive effects of H2S. This review also summarizes the state of research on H2S and hypertension in China. A better understanding of the role of H2S in hypertension and related cardiovascular diseases will allow novel strategies to be devised for their treatment.
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This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
As the most abundant natural flavonoid in rattan tea, dihydromyricetin (DMY) has shown a wide range of pharmacological effects. In addition to the general characteristics of flavonoids, DMY has the ...effects of cardioprotection, anti-diabetes, hepatoprotection, neuroprotection, anti-tumor, and dermatoprotection. DMY was also applied for the treatment of bacterial infection, osteoporosis, asthma, kidney injury, nephrotoxicity and so on. These effects to some extent enrich the understanding about the role of DMY in disease prevention and therapy. However, to date, we still have no outlined knowledge about the detailed mechanism of DMY, which might be related to anti-oxidation and anti-inflammation. And the detailed mechanisms may be associated with several different molecules involved in cellular apoptosis, oxidative stress, and inflammation, such as AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), protein kinase B (Akt), nuclear factor-κB (NF-κB), nuclear factor E2-related factor 2 (Nrf2), ATP-binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor-γ (PPARγ) and so on. Here, we summarized the current pharmacological developments of DMY as well as possible mechanisms, aiming to push the understanding about the protective role of DMY as well as its preclinical assessment of novel application.
Sclerotia of Wolfiporia hoelen are one of the most important traditional Chinese medicines and are commonly used in China, Japan, Korea, and other Asian countries. In the present study, we presented ...the first high-quality homokaryotic genome of W. hoelen with 14 chromosomes which was evaluated with assembly index, telomere position detection, and whole-genome collinearity. A 64.44 Mb genome was assembled with a Contig N50 length of 3.76 Mb. The imbalanced distribution of transposons and chromosome characters revealed the probable two-speed genome of W. hoelen. High consistency between methylation and transposon conserved the genome stability. The expansion of the gene family about signal transduction and nutritional transport has intimate relationships with sclerotial formation. Up-regulation of expression for distinctive decomposition enzymes, ROS clearance genes, biosynthesis of unsaturated fatty acids, and change of the cell wall components maintained high-speed growth of mycelia that may be the high-temperature adaption strategy of W. hoelen. Further, the analysis of mating-control genes demonstrated that HD3 probably had no function on mating recognition, with the HD protein in a distant genetic with known species. Overall, the high-quality genome of W. hoelen provided crucial information for genome structure and stability, high-temperature adaption, and sexual and asexual process.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Diabetes mellitus is a metabolic disease caused by disorders of insulin secretion and utilization. Long-term hyperglycemia, insulin resistance, and disorders of glucose and lipid metabolism cause ...vascular endothelial cell damage. Endothelial dysfunction is a key feature of diabetic vascular complications such as diabetic nephropathy, retinopathy, neuropathy, and atherosclerosis. Importantly, cell death is thought to be a key factor contributing to vascular endothelial injury. Morphologically, cell death can be divided into three forms: type I apoptosis, type II autophagy, and type III necrosis. According to the difference in function, cell death can be divided into accidental cell death (ACD) and regulated cell death (RCD). RCD is a controlled process involving numerous proteins and precise signaling cascades. Multiple subroutines covered by RCD may be involved in diabetic endothelial dysfunction, including apoptosis, autophagy, necroptosis, pyroptosis, entosis, ferroptosis, ferroautophagy, parthanatos, netotic cell death, lysosome-dependent cell death, alkaliptosis, oxeiptosis, cuproptosis, and PANoptosis. This article briefly reviews the mechanism and significance of cell death associated with diabetic endothelial dysfunction, which will help deepen the understanding of diabetic endothelial cell death and provide new therapeutic ideas.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The physiological role of Rho-specific guanine nucleotide dissociation inhibitor (RhoGDI) in vascular remodeling remains unknown. We investigated the function of RhoGDI in angiotensin II (Ang ...II)-induced vascular remodeling in cultured human aortic vascular smooth muscle cells (HA-VSMCs) and in an Ang II-infusion vascular remodeling mouse model.
For in vitro assays of HA-VSMCs, proliferation was assessed by BrdU and EdU assays and immunofluorescence analysis of ki-67 expression. RhoGDI1 and RhoGDI2 function and expression were assessed by RNAi, Western blotting and real-time RT-PCR. RhoGDI ubiquitination and SUMOylation levels were evaluated by co-immunoprecipitation and Western blotting. The functions of proteosomal-mediated degradation, ubiquitination, SUMOylation and Ang II receptors were assessed using specific inhibitors. To evaluate the in vivo effects of Ang II and RhoGDI, H & E staining, Masson's trichrome staining, and immunostaining were employed.
Ang II treatment of HA-VSMCs for 6 or 48 h promoted RhoGDI1 and RhoGDI2 protein degradation and reduced cell proliferation, which was reversed by proteosome inhibition. In contrast, treatment with Ang II for 12 or 24 h induced dose-dependent cell proliferation without affecting RhoGDI expression. RNA interference of either RhoGDI1 or RhoGDI2 blocked proliferation induced by 12 or 24 h treatment of Ang II. Moreover, Ang II-dependent degradation at 6 and 48 h correlated with RhoGDI ubiquitination and inversely correlated with RhoGDI SUMOylation and cell proliferation. Treatment with specific inhibitors suggests that ubiquitin and SUMO competitively bind to RhoGDI1 and RhoGDI2 to reciprocally regulate RhoGDI stability and HA-VSMC proliferation. Furthermore, inhibition of the Ang II receptor 1 (AT1 receptor), but not the Ang II receptor 2, blocked Ang II-dependent RhoGDI stabilization and proliferation at 12 and 24 h. In mice, Ang II infusion increased the intima-media thickness, collagen and myofiber production and VSMC proliferation, and these effects were shown to be dependent on RhoGDI1, RhoGDI2 and AT1 receptor. Ang II infusion exerted no significant effect on RhoGDI1 and RhoGDI2 protein levels, which were decreased after AT1 receptor inhibition.
Together, the results of this study reveal a novel mechanism by which Ang II regulates RhoGDI stability by SUMOylation and ubiquitination via AT1 receptor activation and thus affects VSMC proliferation and vascular remodeling.
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•The stability of RhoGDI1 and RhoGDI2 participates in AngII-mediated smooth muscle phenotypic transformation and vascular remodeling.•SUMOylation and ubiquitination reciprocally regulate RhoGDI stability via the AT1 receptor.•RhoGDI targeted degradation may provide a novel approach for treatment of vascular remodeling.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cells communication in response to extracellular or biophysical stimulus relies on elaborated systems of signal transduction. In the course of most signal pathway, the cascades involve signal protein ...complexes, which are often assembled by adaptor proteins. Tumor necrosis factor receptor type 1-associated death domain protein (TRADD) is an adaptor molecule involved in various signal pathways and mediating multiple biological activities, including cell survival, cell proliferation, cell differentiation, apoptosis, necroptosis and inflammation. TRADD contains an N terminal tumor necrosis factor receptor-associated factor 2 (TRAF2) binding domain and a C terminal death domain (DD) for interacting with multiple DD-containing proteins. Following activation of specific receptors, such as tumor necrosis factor receptor 1 (TNFR1), death receptor 3 (DR3), tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAILR1, DR4), TRAILR1 (DR5), DR6 and p75 neurotrophin receptor (p75NTR)，TRADD can bind to the receptors, serving as a platform for the recruitment of the downstream molecules for signal propagating and thus mediating various physiological and pathological processes. In this review, we provide a brief overview of the current knowledge on TRADD and discuss the roles of TRADD in infectious and inflammatory diseases, cardiovascular diseases, central nervous system diseases, cancer, endometriosis, hepatocyte proliferation, preterm birth and perinatal development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
BACKGROUND:S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role ...of SNO of MLP (muscle LIM protein) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload.
METHODS:Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. SNO sites were further identified through liquid chromatography–tandem mass spectrometry. Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry and confirmed by coimmunoprecipitation. Recruitment of TLR3 (Toll-like receptor 3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA–transfected neonatal rat cardiomyocytes and in a TLR3 knockout mouse model.
RESULTS:SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction. The level of SNO-MLP also increased in angiotensin II– or phenylephrine-treated neonatal rat cardiomyocytes. S-nitrosylated site of MLP at cysteine 79 was identified by liquid chromatography–tandem mass spectrometry and confirmed in neonatal rat cardiomyocytes. Mutation of cysteine 79 significantly reduced hypertrophic growth in angiotensin II– or phenylephrine-treated neonatal rat cardiomyocytes and transverse aortic constriction mice. Reducing SNO-MLP level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, SNO-MLP stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupted this interaction by downregulating TLR3-attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and RIP3 (receptor-interacting protein kinase 3). This interaction in turn induced NLRP3 (nucleotide-binding oligomerization domain–like receptor pyrin domain containing 3) inflammasome activation, thereby promoting the development of myocardial hypertrophy.
CONCLUSIONS:Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a therapeutic target for myocardial hypertrophy and heart failure.
Dihydromyricetin (DMY) is one of the most important flavonoids in vine tea, which showed several pharmacological effects. However, information about the potential role of DMY on angiotensin II (Ang ...II) induced cardiac fibroblasts proliferation remains unknown. In the present study, cardiac fibroblasts isolated from neonatal Sprague-Dawley rats were pretreated with different concentrations of DMY (0–320μM) for 4h, or DMY (80μM) for different time (0–24h), followed by Ang II (100nM) stimulation for 24h, Then number of cardiac fibroblasts and content of hydroxyproline was measured. The level of cellular reactive oxygen species, malondialdehyde (MDA), activity of superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were also evaluated. Expression of type I, type III collagen, α-smooth muscle actin (α-SMA), p22phox (one vital subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase), SOD and thioredoxin (Trx) were detected with real time PCR or/and western blot. We found that pre-incubation with DMY (20μM, 40μM, 80μM) for 4h, 12h or 24h attenuated the proliferation of cardiac fibroblasts induced by Ang II. Expression of type I and type III collagen, as well as α-SMA were inhibited by DMY at both mRNA and protein level. DMY also significantly decreased cellular reactive oxygen species production and MDA level, while increased the SOD activity and T-AOC. DMY suppressed p22phox, while enhanced antioxidant SOD and Trx expression in Ang II stimulated cardiac fibroblasts. Thus, dihydromyricetin attenuated Ang II induced cardiac fibroblasts proliferation related to inhibitory of oxidative stress.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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