cytochrome-c-t and Hypertrophy

To investigate the effect of Xuezhikang (, XZK) on renal cell apoptosis in diabetic rats and the possible mechanism.. Sixty-six rats were randomly divided into 3 groups: the normal, model and XZK groups. In each group, the rats were further randomly divided into 3-month and 6-month subgroups, respectively. Diabetes of rats was induced by a single intraperitoneal injection of 1% streptozocin at 60 mg/kg body weight. Rats in the XZK group received gastric perfusion of XZK (1200 mg/kg body weight) everyday for 3 or 6 months, while rats in the normal and model groups received equal volume of saline. Twenty-four hours' urine was collected for urinary albumin excretion (UAE) measurement. Periodic acid-Schiff (PAS) and Masson's trichrome staining were used for saccharides and collagen detection. Cell apoptosis of renal cortex was investigated by TdT-mediated dUTP nick end labeling (TUNEL) staining. Bax and Bcl-2 expressions were detected by immunohistochemistry and Western blot, respectively. Cytochrome C (Cyt C) and caspase-9 concentration were detected by Western blot.. Compared with the model group, XZK treatment could significantly decrease the kidney hypertrophy index, 24 h UAE, renal cell apoptosis, cytoplasmic Cyt C level and active caspase-9 level, as well as suppress the increment of Bax and up-regulate the expression of Bcl-2, leading to the suppression of Bax/Bcl-2 ratio at 3 and 6 months (P<0.05 or P<0.01). Moreover, XZK treatment could alleviate the deposition of PAS-stained saccharides and Masson's trichromestained collagen to different extent.. Renal cell apoptosis was observed in diabetic kidney, in which mitochondrial apoptotic pathway might be involved. XZK treatment could attenuate pathological changes in diabetic kidney and reduce renal cell apoptosis, probably via the suppression of Bax/Bcl-2 ratio, which lead to inhibition of Cyt C release and following caspase-9 activation.

Topics: Albuminuria; Animals; Apoptosis; bcl-2-Associated X Protein; Blood Glucose; Caspase 9; Cytochromes c; Diabetes Mellitus, Experimental; Drugs, Chinese Herbal; Hypertrophy; In Situ Nick-End Labeling; Kidney; Kidney Glomerulus; Lipids; Male; Mesangial Cells; Proto-Oncogene Proteins c-bcl-2; Rats, Sprague-Dawley; Streptozocin

Despite the availability of many pharmacological and mechanical therapies, the mortality rate among patients with congestive heart failure (CHF) remains high. We tested the hypothesis that TVP1022 (the S-isomer of rasagiline; Azilect), a neuroprotective and cytoprotective molecule, is also cardioprotective in the settings of experimental CHF in rats.. In rats with volume overload-induced CHF, we investigated the therapeutic efficacy of TVP1022 (7.5 mg/kg) on cardiac function, structure, biomarkers, and kidney function. Treatment with TVP1022 for 7 days before CHF induction prevented the increase in left ventricular end-diastolic area and end-systolic area, and the decrease in fractional shortening measured 14 days after CHF induction. Additionally, TVP1022 pretreatment attenuated CHF-induced cardiomyocyte hypertrophy, fibrosis, plasma and ventricular B-type natriuretic peptide levels, and reactive oxygen species expression. Further, in CHF rats, TVP1022 decreased cytochrome c and caspase 3 expression, thereby contributing to the cardioprotective efficacy of the drug. TVP1022 also enhanced the urinary Na(+) excretion and improved the glomerular filtration rate. Similar cardioprotective effects were obtained when TVP1022 was given to rats after CHF induction.. TVP1022 attenuated the adverse functional, structural, and molecular alterations in CHF, rendering this drug a promising candidate for improving cardiac and renal function in this disease state.

Topics: Animals; Cardiotonic Agents; Caspase 3; Cytochromes c; Disease Models, Animal; Fibrosis; Glomerular Filtration Rate; Heart Failure; Hypertrophy; Indans; Kidney; Myocytes, Cardiac; Natriuretic Peptide, Brain; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Ventricular Remodeling

Transgenic mice with cardiac-restricted overexpression of secretable TNF (MHCsTNF) develop progressive LV wall thinning and dilation accompanied by an increase in cardiomyocyte apoptosis and a progressive loss of cytoprotective Bcl-2. To test whether cardiac-restricted overexpression of Bcl-2 would prevent adverse cardiac remodeling, we crossed MHCsTNF mice with transgenic mice harboring cardiac-restricted overexpression of Bcl-2. Sustained TNF signaling resulted in activation of the intrinsic cell death pathway, leading to increased cytosolic levels of cytochrome c, Smac/Diablo and Omi/HtrA2, and activation of caspases -3 and -9. Cardiac-restricted overexpression of Bcl-2 blunted activation of the intrinsic pathway and prevented LV wall thinning; however, Bcl-2 only partially attenuated cardiomyocyte apoptosis. Subsequent studies showed that c-FLIP was degraded, that caspase-8 was activated, and that Bid was cleaved to t-Bid, suggesting that the extrinsic pathway was activated concurrently in MHCsTNF hearts. As expected, cardiac Bcl-2 overexpression had no effect on extrinsic signaling. Thus, our results suggest that sustained inflammation leads to activation of multiple cell death pathways that contribute to progressive cardiomyocyte apoptosis; hence the extent of such programmed myocyte cell death is a critical determinant of adverse cardiac remodeling.

Topics: Animals; Apoptosis; Caspases; Cytochromes c; Enzyme Activation; Humans; Hypertrophy; Mice; Myocytes, Cardiac; Proto-Oncogene Proteins c-bcl-2; Tumor Necrosis Factor-alpha; Ventricular Remodeling

This study tested the hypothesis that loading decreased apoptosis in skeletal muscle in an aging-dependent fashion. One wing of young and aged Japanese quails was loaded for 7 or 21 days to induce hypertrophy. The contralateral wing served as the intra-animal control. Loading increased fast-twitch quail patagialis muscle mass by 28 and 49%, after 7 or 21 days of loading, respectively in young adult birds. Muscle mass was not elevated after 7 days of loading, but increased by 29% after 21 days of loading in aged birds. Seven days of loading reduced DNA fragmentation and cytosolic accumulation of cytochrome c in muscles from young birds but not in muscles from aged birds. ARC protein content was lower and H2O2 content was higher in muscles from aged birds following 7 days of loading. The mitochondria-free cytosolic protein fraction from muscles loaded for 7 days had 41 and 29% lower AIF content than control muscles in young and aged birds, respectively. XIAP, an apoptotic suppressor protein increased after 7 days of loading in muscles from young adult but not aged birds. Our results suggest that loading suppresses pro-apoptotic signaling in quail muscle but aging delays or attenuates these anti-apoptotic changes.

Topics: Aging; Animals; Apoptosis; Apoptosis Inducing Factor; Apoptosis Regulatory Proteins; Biomarkers; Coturnix; Cytochromes c; Cytosol; Hydrogen Peroxide; Hypertrophy; In Situ Nick-End Labeling; Male; Muscle Fibers, Fast-Twitch; Muscle, Skeletal; Signal Transduction; Time Factors; Weight-Bearing; X-Linked Inhibitor of Apoptosis Protein

Oxidative stress stimulates both growth and apoptosis in cardiac myocytes in vitro. We investigated the role of oxidative stress in the initial phases of cardiac remodeling induced in an animal model by volume overload. As plausible candidates for a connection between oxidative stress and cardiomyocyte apoptosis or hypertrophy, we explored the behaviour of two MAPKs, specifically JNK and ERK. At 48 h of overload, the greatest increase in oxidative stress coincided with a peak of cardiomyocyte apoptosis. This was possibly induced through the mitochondrial metabolism, as evidenced by the release of cytochrome c and a significant increase in the active forms of caspase-9 and -3, but not caspase-8. Oxidative stress markers significantly decreased at 96 h of overload, combined with a marked attenuation of apoptosis and the appearance of hypertrophy. The highest levels of JNK and the lowest levels of ERK phosphorylation were observed at 48 h of overload. Conversely, a sharp increase in ERK phosphorylation was detected at 96 h of overload coinciding with the hypertrophic response. Together these results show that oxidative stress is an early and transient event in myocardial volume overload. They suggest that oxidative stress mediates amplitude dependent apoptotic and hypertrophic responses in cardiomyocytes through the selective activation of, respectively, JNK and ERK.

Topics: Animals; Apoptosis; Cardiac Volume; Caspase 3; Caspase 9; Caspases; Cell Size; Cytochromes c; Echocardiography; Enzyme Activation; Hemodynamics; Hypertrophy; JNK Mitogen-Activated Protein Kinases; Malondialdehyde; Mitogen-Activated Protein Kinases; Myocytes, Cardiac; Oxidative Stress; Phosphorylation; Poly(ADP-ribose) Polymerases; Subcellular Fractions; Sus scrofa; Time Factors

In the present study, we examined the responses of apoptosis and apoptotic regulatory factors to muscle hypertrophy induced by stretch overload in quail slow-tonic muscles. The wings from one side of young and aged Japanese quails were loaded by attaching a tube weight corresponding to 12% of the bird's body weight for 7 or 21 days. Muscle from the contralateral side served as the intraanimal control. Relative to the intraanimal contralateral control side, the muscle wet weight increased by 96% in young birds, whereas the muscle weight gain in aged birds was not significant after 7 days of loading. After 21 days of loading, muscle weight significantly increased by 179% and 102% in young and aged birds, respectively. Heat shock protein (HSP)72 and HSP27 protein contents in the loaded sides were higher than on the control sides exclusively in young birds after 7 days of loading. Compared with the contralateral control muscle, the extent of apoptotic DNA fragmentation and the total cytosolic apoptosis-inducing factor protein content were reduced in all loaded muscles except for the 7-day-loaded muscles from the aged birds. Bax protein content was diminished in the loaded muscle relative to the control side from all groups, whereas Bcl-2 protein content was reduced in the young and aged muscles after 21 days of loading. The total cytosolic cytochrome c protein content was decreased and the X chromosome-linked inhibitor of apoptosis protein content was elevated in 7- and 21-day-loaded muscles relative to the intraanimal control muscle from young birds. Furthermore, after 7 days of loading the muscles of aged birds, H(2)O(2) content and the total cytosolic protein content of second mitochondrial activator of caspases/direct inhibitor of apoptosis-binding protein with low isoelectric point were elevated compared with the intraanimal control side. These data suggest that stretch overload-induced muscle hypertrophy is associated with changes in apoptosis in slow-tonic skeletal muscle. Moreover, discrepant apoptotic responses to muscle overload in young and aged muscles may account in part for the age-related decline in the capability for muscle hypertrophy.

Topics: Aging; Animals; Apoptosis; Apoptosis Inducing Factor; bcl-2-Associated X Protein; Coturnix; Cytochromes c; DNA Fragmentation; Flavoproteins; Heat-Shock Proteins; Hydrogen Peroxide; Hypertrophy; Membrane Proteins; Muscle Fibers, Slow-Twitch; Muscle Proteins; Muscle, Skeletal; Proteins; Proto-Oncogene Proteins c-bcl-2; Superoxide Dismutase; X-Linked Inhibitor of Apoptosis Protein