The coexistence of nocturnal sustained hypoxia and obesity additively increases cardiac apoptosis

2008 ◽  
Vol 104 (4) ◽  
pp. 1144-1153 ◽  
Author(s):  
Shin-Da Lee ◽  
Wei-Wen Kuo ◽  
Da-Tian Bau ◽  
Fu-Yang Ko ◽  
Fong-Li Wu ◽  
...  
Keyword(s):  
Death Receptor ◽  
Left Ventricular ◽  
Heart Weight ◽  
Apoptotic Pathway ◽  
Apoptotic Protein ◽  
Blood Pressures ◽  
Old Rats ◽  
Apoptotic Pathways ◽  
Whole Heart ◽  
Sustained Hypoxia

Background: nocturnal sustained hypoxia during sleeping time has been reported in severe obesity, but no information regarding the cardiac molecular mechanism in the coexistence of nocturnal sustained hypoxia and obesity is available. This study evaluates whether the coexistence of nocturnal sustained hypoxia and obesity will increase cardiac Fas death receptor and mitochondrial-dependent apoptotic pathway. Methods: 32 lean and 32 obese 5- to 6-mo-old rats with or without nocturnal sustained hypoxia were studied and assigned to one of four subgroups: normoxia lean (NL), normoxia obese (NO), hypoxia lean (HL, 12% O2 for 8 h and 21% O2 16 h/day, 1 wk), and hypoxia obese (HO). The heart weight index, tail cuff plethysmography, echocardiography, hematoxylin-eosin staining, TUNEL assays, Western blotting, and RT-PCR were performed. Results: systolic and diastolic blood pressures in HO were higher than those in NL, and fractional shortening in HO was reduced compared with others. The whole heart weight, the left ventricular weight, the abnormal myocardial architecture, and TUNEL-positive apoptotic cells, as well as the activity of cardiac Fas-dependent and mitochondrial-dependent apoptotic pathway, were significantly increased in obese group or nocturnal sustained hypoxia group and were further increased when obesity and nocturnal sustained hypoxia coexisted, the evidence for which is based on decreases in an anti-apoptotic protein Bcl2 level and Bid and increases in Fas, FADD, pro-apoptotic Bad, BNIP3, cytosolic cytochrome c, activated caspase-8, activated caspase-9, and activated caspase-3. Conclusions: The cardiac Fas receptor- and mitochondrial-dependent apoptotic pathways were more activated in obesity with coexistent nocturnal sustained hypoxia, which may represent one possible apoptotic mechanism for the development of heart failure in obesity with nocturnal sustained hypoxia.

scholarly journals Inhibition of Cardiac Hypertrophy Effects in D-Galactose-Induced Senescent Hearts byAlpinate Oxyphyllae FructusTreatment

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Yung-Ming Chang ◽  
Hen-Hong Chang ◽  
Hung-Jen Lin ◽  
Chin-Chuan Tsai ◽  
Chuan-Te Tsai ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Rat Model ◽  
Cerebrovascular Disorders ◽  
Treated Group ◽  
Left Ventricular ◽  
Heart Weight ◽  
Dependent Manner ◽  
Signaling Mechanism ◽  
Aging Rat ◽  
Whole Heart

Aging is a complex physiological phenomenon accelerated by ROS accumulation, with multisystem decline and increasing vulnerability to degenerative diseases and death. Cardiac hypertrophy is a key pathophysiological component that accompanies the aging process. Alpinate Oxyphyllae Fructus (Alpinia oxyphyllaMIQ, AOF) is a traditional Chinese medicine, which provides cardioprotective activity against aging, hypertension, and cerebrovascular disorders. In this study, we found the protective effect of AOF against cardiac hypertrophy in D-galactose-induced aging rat model. The results showed that treating rats with D-galactose resulted in pathological hypertrophy as evident from the morphology change, increased left ventricular weight/whole heart weight, and expression of hypertrophy-related markers (MYH7 and BNP). Both concentric and eccentric cardiac hypertrophy signaling proteins were upregulated in aging rat model. However, these pathological changes were significantly improved in AOF treated group (AM and AH) in a dose-dependent manner. AOF negatively modulated D-galactose-induced cardiac hypertrophy signaling mechanism to attenuate ventricular hypertrophy. These enhanced cardioprotective activities following oral administration of AOF reflect the potential use of AOF for antiaging treatments.

scholarly journals Ophiopogon japonicas (Linn. f.) Ker-Gawl. extract ameliorates chronic heart failure in rats

2021 ◽  
Vol 18 (9) ◽  
pp. 1853-1857
Author(s):  
Hu-zhi Cai ◽  
Yan-ping Tang ◽  
Xin-yu Chen ◽  
Hai-bo Xie ◽  
Qing-yang Chen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Normal Control Group ◽  
Heart Weight ◽  
Control Group ◽  
High Dose ◽  
Chronic Congestive Heart Failure ◽  
Whole Heart

Purpose: To investigate the effect of Ophiopogon japonicas (Linn. f.) Ker-Gawl. extract (OJKE) on oxidative stress and hemodynamics in chronic congestive heart failure (CHF) rats. Methods: The rats were modelled to congestive heart failure (except normal group) , and then randomly divided into normal control group, model (untreated) group, captopril group, high-dose, middle-dose and low-dose of OJKE groups. They were treated for 4 weeks as appropriate for each group. At the end of treatment, the hemodynamic function, whole heart weight index, and blood creatinine kinase (CK), as well as superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), nitricoxide synthase (NOS) were determined. Results: Compared with the normal control group, arterial systolic pressure (SBP), diastolic pressure (DBP), mean arterial pressure (MAP), heart rate (HR), left ventricular systolic peak (LVSP), and left ventricular pressure change rate (dp/dt max) significantly decreased (p < 0.05), while left ventricular end diastolic pressure (LVEDP), whole heart weight index, blood CK, MDA, NO, NOS significantly increased in the untreated group (p < 0.05). A high dose of OJKE significantly improved hemodynamic function, lowered MDA (8.33 ± 2.12 nmol/mL) and NO (20.58 ± 3.53 umol/L) levels (p < 0.05), and also decreased CK (0.53±0.37 U/mL) and NOS (22.46±3.29 U/mL) in CHF rats (p < 0.05). Conclusion: OJKE improved adriamycin-induced chronic congestive heart failure in rats significantly.

Effect of Zhen-wu decoction on chronic heart failure in rats

2017 ◽  
Vol 16 (10) ◽  
pp. 2439-2443
Author(s):  
Zhongyong Liu ◽  
Lin Li ◽  
Shihua Luo ◽  
Jia Fang
Keyword(s):  
Heart Failure ◽  
Diastolic Pressure ◽  
Left Ventricular ◽  
Normal Control Group ◽  
Heart Weight ◽  
Control Group ◽  
High Dose ◽  
Chronic Congestive Heart Failure ◽  
Hemodynamic Function ◽  
Whole Heart

Purpose: To investigate the effect of Zhen-wu decoction (ZWD) on oxidative stress and hemodynamics in chronic congestive heart failure (CHF) rats.Methods: After Sprague Dawley (SD) rats were successfully prepared into CHF, they were randomly divided into normal control group, model (untreated CHF) group,  captopril group, high-dose, middledose and low-dose of ZWD groups, and were  treated with drugs for 4 weeks respectively. At the end of the experiment,  hemodynamic function, whole heart weight index, blood creatinine kinase (CK), superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and nitric oxide synthase (NOS) were determined.Results: Compared with normal control group, ZWD group showed decreased arterial systolic pressure (SBP, 89.16 ± 17.27 mmHg), diastolic pressure (DBP, 72.54 ± 22.36 mmHg), mean arterial pressure (MAP, 72.64 ± 11.87 mmHg), heart rate (HR, 368.25 ± 39.12 beats/min), left ventricular systolic peak (LVSP, 105.27 ± 15.23 mmHg), and left ventricular pressure change rate (dp/dt max) (p < 0.05), while left ventricular end diastolic pressure (LVEDP) (19.52 ± 1.89 mmHg), whole heart weight index (2.74 ± 0.16 mg/g), blood CK (0.98 ± 0.16 U/mL), MDA (17.28 ± 2.94 nmol/mL), NO (36.35 ± 3.27 umol/L), NOS (39.89 ± 3.56 U/mL) significantly  increased (p < 0.05). High dose of ZWD significantly improved hemodynamic  function, lowered MDA (8.85 ± 2.14 nmol/mL) and NO (24.25 ± 3.21 umol/L) levels (p < 0.05), and also decreased CK (0.58 ± 0.37 U/mL) and NOS (26.12 ± 3.87 U/mL) in CHF rats (p < 0.05).Conclusion: ZWD improves adriamycin-induced chronic congestive heart failure in rats significantly, and therefore has potential to be developed for the management of chronic congestive heart failure.Keywords: Zhen-wu decoction, Chronic heart failure, Hemodynamic function,  Oxidative stress

scholarly journals Therapeutics Targeting the Core Apoptotic Machinery

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2618
Author(s):  
Claudia Hamilton ◽  
Jennifer P. Fox ◽  
Daniel B. Longley ◽  
Catherine A. Higgins
Keyword(s):  
Cancer Cells ◽  
Death Receptor ◽  
Cancer Therapeutics ◽  
Clinical Development ◽  
Apoptotic Pathway ◽  
Resistance Factors ◽  
Anti Cancer ◽  
Apoptosis Pathways ◽  
Direct Targeting ◽  
Apoptotic Pathways

Therapeutic targeting of the apoptotic pathways for the treatment of cancer is emerging as a valid and exciting approach in anti-cancer therapeutics. Accumulating evidence demonstrates that cancer cells are typically “addicted” to a small number of anti-apoptotic proteins for their survival, and direct targeting of these proteins could provide valuable approaches for directly killing cancer cells. Several approaches and agents are in clinical development targeting either the intrinsic mitochondrial apoptotic pathway or the extrinsic death receptor mediated pathways. In this review, we discuss the main apoptosis pathways and the key molecular targets which are the subject of several drug development approaches, the clinical development of these agents and the emerging resistance factors and combinatorial treatment approaches for this class of agents with existing and emerging novel targeted anti-cancer therapeutics.

Tissue-fluid pressure measured in perfused rabbit hearts during osmotic transients

1987 ◽  
Vol 252 (6) ◽  
pp. H1127-H1137 ◽  
Author(s):  
S. E. Anderson ◽  
J. A. Johnson
Keyword(s):  
Linear Regression Analysis ◽  
Fluid Pressure ◽  
Left Ventricular ◽  
Heart Weight ◽  
Tissue Fluid ◽  
Mean Values ◽  
Solute Permeability ◽  
Tissue Compliance ◽  
Crystalloid Solutions ◽  
Whole Heart

To resolve discrepancies between models used to calculate myocardial capillary solute permeability we measured tissue-fluid pressure (Pi), perfusion pressure (Pp), and heart weight continuously after a step change in the NaCl or inulin concentration of crystalloid solutions perfusing isolated rabbit hearts. Linear regression analysis of the mean values for near steady-state Pi plotted against Pp showed significantly different (P less than 0.01) slopes of 0.77 and 0.40, respectively, for the inner and outer halves of the left ventricular free wall. Tissue compliance (Tcm) was measured as the fractional change in whole heart weight divided by the concurrent change in Pi. For NaCl and inulin osmotic transients Tcm values were 0.005 +/- 0.001 (SE) and 0.014 +/- 0.004 ml X cmH2O-1 X g tissue-1, respectively. A model for heart weight change based on the Starling hypothesis predicts significantly different tissue compliance (Tcc) values of 0.031 +/- 0.004 and 0.040 +/- 0.005 ml X cmH2O-1 X g tissue-1 for the same transients, respectively. This model shows myocardial capillary permeability for inulin and NaCl are overestimated by 25% if tissue compliance is not included in the analysis. The discrepancy between Tcm and Tcc is discussed.

scholarly journals A Death Receptor-associated Anti-apoptotic Protein, BRE, Inhibits Mitochondrial Apoptotic Pathway

2004 ◽  
Vol 279 (50) ◽  
pp. 52106-52116 ◽  
Author(s):  
Qing Li ◽  
Arthur Kar-Keung Ching ◽  
Ben Chung-Lap Chan ◽  
Stephanie Ka-Yee Chow ◽  
Pak-Leong Lim ◽  
...  
Keyword(s):  
Tumor Necrosis Factor Receptor ◽  
Death Receptor ◽  
Cellular Level ◽  
Down Regulation ◽  
Apoptotic Pathway ◽  
Signaling Complex ◽  
Apoptotic Protein ◽  
Tnf Α ◽  
Receptor Ligation ◽  
Interfering Rna

BRE,brain andreproductive organ-expressed protein, was found previously to bind the intracellular juxtamembrane domain of a ubiquitous death receptor, tumor necrosis factor receptor 1 (TNF-R1), and to down-regulate TNF-α-induced activation of NF-κB. Here we show that BRE also binds to another death receptor, Fas, and upon overexpression conferred resistance to apoptosis induced by TNF-α, anti-Fas agonist antibody, cycloheximide, and a variety of stress-related stimuli. However, down-regulation of the endogenous BRE by small interfering RNA increased apoptosis to TNF-α, but nottoetoposide, indicating that the physiological antiapoptotic role of this protein is specific to death receptor-mediated apoptosis. We further demonstrate that BRE mediates antiapoptosis by inhibiting the mitochondrial apoptotic machinery but without translocation to the mitochondria or nucleus or down-regulation of the cellular level of truncated Bid. Dissociation of BRE rapidly from TNF-R1, but not from Fas, upon receptor ligation suggests that this protein interacts with the death inducing signaling complex during apoptotic induction. Increased association of BREwith phosphorylated, sumoylated, and ubiquitinated proteins after death receptor stimulation was also detected. We conclude that in contrast to the truncated Bid that integrates mitochondrial apoptosis to death receptor-triggered apoptotic cascade, BRE inhibits the integration. We propose that BRE inhibits, by ubiquitination-like activity, components in or proximal to the death-inducing signaling complexes that are necessary for activation of the mitochondria.

scholarly journals Broussochalcone A Is a Novel Inhibitor of the Orphan Nuclear Receptor NR4A1 and Induces Apoptosis in Pancreatic Cancer Cells

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2316
Author(s):  
Hyo-Seon Lee ◽  
Soo-Hyun Kim ◽  
Bo-Mi Kim ◽  
Stephen Safe ◽  
Syng-Ook Lee
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Nuclear Receptor ◽  
Human Pancreatic Cancer ◽  
Orphan Nuclear Receptor ◽  
Apoptotic Pathway ◽  
Pancreatic Cancer Cells ◽  
Apoptotic Protein ◽  
Apoptotic Pathways ◽  
Specificity Protein

The orphan nuclear receptor 4A1 (NR4A1) is overexpressed in pancreatic cancer and exhibits pro-oncogenic activity, and NR4A1 silencing and treatment with its inactivators has been shown to inhibit pancreatic cancer cells and tumor growth. In this study, we identified broussochalcone A (BCA) as a new NR4A1 inhibitor and demonstrated that BCA inhibits cell growth partly by inducing NR4A1-mediated apoptotic pathways in human pancreatic cancer cells. BCA downregulated specificity protein 1 (Sp1)-mediated expression of an anti-apoptotic protein, survivin, and activated the endoplasmic reticulum (ER) stress-mediated apoptotic pathway. These results suggest that NR4A1 inactivation contributes to the anticancer effects of BCA, and that BCA represents a potential anticancer agent targeting NR4A1 that is overexpressed in many types of human cancers.

scholarly journals Exercise training inhibits left ventricular collagen upregulation in mice with hypertrophic cardiomyopathy

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
K Andreassen ◽  
C L Rixon ◽  
A Hasic ◽  
I M Hauge-Iversen ◽  
G Christensen ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Exercise Training ◽  
Sedentary Behaviour ◽  
High Intensity ◽  
Fold Increase ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Heart Weight ◽  
Lung Weight ◽  
Whole Heart

Abstract Background Hypertrophic cardiomyopathy (HCM) is estimated to affect 1:500, and is characterised by otherwise unexplained left ventricular (LV) hypertrophy, cardiomyocyte disarray, fibrosis, diastolic dysfunction, and ventricular arrhythmias. Historically, patients with HCM have been discouraged from participation in high intensity sports and exercise. However, the 2020 Sports Cardiology Guidelines recommend that patients with HCM should receive advice about exercise training (ET) based on individual risk assessment. To learn more about the effects of ET in HCM, we exposed mice carrying an HCM-causative sarcomere mutation (Myh6R403Q/+ (R403Q) mice) to high intensity interval training. Purpose To investigate the effect of exercise training on hypertrophic cardiomyopathy in mice. Methods R403Q mice were stratified to treadmill exercise (n=11) or sedentary behaviour (n=11). After 3 weeks, we induced HCM by giving CsA in the feed for 3 weeks, while the ET or sedentary behaviour continued for a total of 6 weeks. Each bout of treadmill running consisted of a 10-minute warm up, followed by 5 intervals of 8 minutes at high intensity (90% of VO2 max speed at week 0) and 2 minutes at medium intensity (60% of VO2 max speed at week 0). Every third day of the ET protocol we increased the high and medium intensity running speeds by 0.6 and 0.4 m/min, respectively. We performed echocardiography after 0, 3, and 6 weeks of the 6-week protocol. After completion of the protocol, we recorded lung and whole heart weight, and harvested LVs for molecular analyses. Results Confirming the expected HCM phenotype, R403Q mice that received CsA (R403Q SED+CsA) had a 1.3-fold increase in whole heart weight (p&lt;0.0001), 1.5-fold increase in lung weight (p&lt;0.001), and 2.4-fold increase in maximal left ventricular posterior wall (LVPW) thickness measured by echocardiography (p&lt;0.0001) compared to sedentary wild type littermates given CsA (WT SED+CsA). Heart weight, lung weight, and maximum LVPW thickness were also increased 1.5- (p&lt;0.0001), 1.6- (p&lt;0.0001), and 2.0-(p&lt;0.0001) fold, respectively, compared to R403Q not given CsA (R403Q SED-CsA). R403Q ET+CsA mice increased their running distance before exhaustion 2.0-fold compared to baseline (p=0.010), and ran 1.6-fold longer than R403Q SED+CsA (p=0.020). In R403Q ET+CsA mice, LV mRNA expression of Col1a2 was 51% (p=0.021), and Col3a1 49% (p=0.013) of R403Q SED+CsA expression levels. Compared to R403Q SED+CsA mice, exercise training did not affect heart weight, maximum LV posterior wall thickness or lung weight in R403Q ET+CsA mice. Conclusion Treadmill ET inhibited upregulation of LV collagen expression in mice with HCM, but did not affect hypertrophy. This could indicate that ET during early development of HCM attenuates development of fibrosis. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): South-Eastern Norway Regional Health Authority (Helse Sør-Øst RHF) and KG Jebsen Cardiac Research Center

scholarly journals A Diamine-PEGylated Oleanolic Acid Derivative Induced Efficient Apoptosis through a Death Receptor and Mitochondrial Apoptotic Pathway in HepG2 Human Hepatoma Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1375
Author(s):  
Fatin Jannus ◽  
Marta Medina-O’Donnell ◽  
Francisco Rivas ◽  
Luis Díaz-Ruiz ◽  
Eva E. Rufino-Palomares ◽  
...  
Keyword(s):  
Oleanolic Acid ◽  
Death Receptor ◽  
Cancer Therapies ◽  
Caspase 9 ◽  
Human Hepatoma Cells ◽  
Apoptotic Pathway ◽  
Cycle Arrest ◽  
Growth Inhibitory ◽  
Apoptotic Pathways ◽  
Oleanolic Acid Derivative

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Our recent studies have shown that the diamine-(PEG)ylated oleanolic acid (OADP) has strong anti-tumor effects in HCCs. In this study, we evaluated the anti-tumor mechanisms of OADP in the HepG2 HCC cell line. The cytotoxicity results showed that HepG2 cell viability was markedly reduced, with a very low 50% of cell growth inhibitory concentration (IC50, 0.14 µg/mL). We then investigated the anti-tumor mechanisms of OADP in HepG2 cells. The flow-cytometry analysis was used to evaluate cell apoptosis, indicating that 74–95% of cells were apoptotic. OADP caused cell cycle arrest in the G0/G1 phase and the loss of the mitochondrial membrane potential (MMP). Western blot analysis was performed to assess the expression levels of key proteins associated with the underlying molecular mechanism. The results showed the clear upregulation of caspase-8, caspase-9, caspase-3, Bak, p21, and p53, accompanied by the downregulation of Bcl-2. Similar results were obtained by the cotreatment with OADP and the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Agents such as OADP, which are capable of activating extrinsic and intrinsic apoptotic pathways, may represent potential HCC cancer therapies.

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