Abstract 123: SUMO1 Modification Regulates SR Calcium ATPase Pump, SERCA2a in Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Changwon Kho ◽  
Ahyoung Lee ◽  
Dongtak Jeong ◽  
Jae Gyun Oh ◽  
Antoine Chaanine ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Calcium Atpase ◽  
Post Translational Modifications ◽  
Beneficial Effects ◽  
Protein Levels ◽  
In Trans ◽  
Underlying Mechanisms ◽  
Hemodynamic Performance ◽  
Reduced Activity

Background: The cardiac calcium ATPase, SERCA2a, is a critical pump responsible for Ca2+ re-uptake during excitation-contraction coupling. Impaired Ca2+ uptake resulting from decreased expression and reduced activity of SERCA2a is a hallmark of heart failure. Accordingly, restoration of SERCA2a expression by gene transfer has proved to be effective in improving cardiac function in heart-failure patients, as well as in animal models. However, the underlying mechanisms of SERCA2a’s dysfunction remain incompletely understood. Methods and Results: In this study, we show that SERCA2a is modified by SUMO1 at lysine sites 480 and 585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability in mouse and human cells. SUMO1 and SERCA2a SUMOylation levels were both decreased in mouse and pig models of heart failure and failing human left ventricles. To determine whether reduced SUMO1 levels are responsible for reduced SERCA2a protein levels and reduced cardiac function, we used an adenovirus associated virus-mediated gene delivery approach to up-regulate SUMO1 in trans aortic constriction-induced mouse model of heart failure. We found that increasing SUMO1 levels led to a restoration of SERCA2a levels, improved hemodynamic performance, and reduced mouse mortality. By contrast, down-regulation of SUMO1 using small hairpin RNA accelerated cardiac functional deterioration and was accompanied by decreased SERCA2a function. Conclusion: In this study, we study a new mechanism for modulation of SERCA2a activity and beneficial effects of SUMO1 in the setting of heart failure. It suggests that changes in post-translational modifications of SERCA2a could negatively affect cardiac function in heart failure. Our data may provide a new platform for the design of therapeutic strategies for heart failure.

scholarly journals Resveratrol, an activator of SIRT1, upregulates sarcoplasmic calcium ATPase and improves cardiac function in diabetic cardiomyopathy

2010 ◽  
Vol 298 (3) ◽  
pp. H833-H843 ◽  
Author(s):  
M. Sulaiman ◽  
M. J. Matta ◽  
N. R. Sunderesan ◽  
M. P. Gupta ◽  
M. Periasamy ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Diabetic Cardiomyopathy ◽  
Calcium Atpase ◽  
Dependent Manner ◽  
Protective Effects ◽  
Progressive Decline ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Dose Dependent

Reduced sarcoplasmic calcium ATPase (SERCA2a) expression has been shown to play a significant role in the cardiac dysfunction in diabetic cardiomyopathy. The mechanism of SERCA2a repression is, however, not known. This study was designed to examine the effect of resveratrol (RSV), a potent activator of SIRT1, on cardiac function and SERCA2a expression in chronic type 1 diabetes. Adult male mice were injected with streptozotocin (STZ) and fed with either a regular diet or a diet enriched with RSV. STZ administration produced progressive decline in cardiac function, associated with markedly reduced SERCA2a and SIRT1 protein levels and increased collagen deposition; RSV treatment to these mice had a tremendous beneficial effect both in terms of improving SERCA2a expression and on cardiac function. In cultured cardiomyocytes, RSV restored SERCA2 promoter activity, which was otherwise highly repressed in high-glucose media. Protective effects of RSV were found to be dependent on its ability to activate Silent information regulator (SIRT) 1. In cardiomyocytes, overexpression of SIRT1 was found sufficient to activate SERCA2 promoter in a dose-dependent manner. In contrast, pretreatment of cardiomyocytes with SIRT1 antagonist, splitomycin, blocked these beneficial effects of RSV. In addition, SIRT1 knockout (+/−) mice were also found to be more sensitive to STZ-induced decline in SERCA2a mRNA. The data demonstrate that, in chronic diabetes, 1) the enzymatic activity of cardiac SIRT1 is reduced, which contributes to reduced expression of SERCA2a and 2) through activation of SIRT1, RSV enhances expression of SERCA2a and improves cardiac function.

scholarly journals Exercise training normalizes elevated firing rate of hypothalamic presympathetic neurons in heart failure rats

2019 ◽  
Vol 316 (2) ◽  
pp. R110-R120 ◽  
Author(s):  
Yiming Shen ◽  
Jin Bong Park ◽  
So Yeong Lee ◽  
Seong Kyu Han ◽  
Pan Dong Ryu
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Firing Rate ◽  
Gaba Release ◽  
Neuronal Firing ◽  
Ventrolateral Medulla ◽  
Patch Clamp Technique ◽  
Electrophysiological Properties ◽  
Beneficial Effects ◽  
Underlying Mechanisms

Exercise training (ExT) normalizes elevated sympathetic nerve activity in heart failure (HF), but the underlying mechanisms are not well understood. In this study, we examined the effects of 3 wk of ExT on the electrical activity of the hypothalamic presympathetic neurons in the brain slice of HF rats. HF rats were prepared by ligating the left descending coronary artery. The electrophysiological properties of paraventricular nucleus neurons projecting to the rostral ventrolateral medulla (PVN-RVLM) were examined using the slice patch-clamp technique. The neuronal firing rate was elevated in HF rats, and ExT induced a reduction in the firing rate ( P < 0.01). This ExT-induced decrease in the firing rate was associated with an increased frequency of spontaneous and miniature inhibitory postsynaptic current (IPSCs; P < 0.05). There was no significant change in excitatory postsynaptic current. Replacing Ca2+ with Mg2+ in the recording solution reduced the elevated IPSC frequency in HF rats with ExT ( P < 0.01) but not in those without ExT, indicating an increase in the probability of GABA release. In contrast, ExT did not restore the reduced GABAA receptor-mediated tonic inhibitory current in HF rats. A GABAA receptor blocker (bicuculline, 20 μM) increased the firing rate in HF rats with ExT ( P < 0.01) but not in those without ExT. Collectively, these results show that ExT normalized the elevated firing activity by increasing synaptic GABA release in PVN-RVLM neurons in HF rats. Our findings provide a brain mechanism underlying the beneficial effects of ExT in HF, which may shed light on the pathophysiology of other diseases accompanied by sympathetic hyperactivation.

scholarly journals Collagen External Scaffolds Mitigate Intimal Hyperplasia and Improve Remodeling of Vein Grafts in a Rabbit Arteriovenous Graft Model

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Haiming Li ◽  
Shoudong Chai ◽  
Longsheng Dai ◽  
Chengxiong Gu
Keyword(s):  
Intimal Hyperplasia ◽  
Nuclear Antigen ◽  
Arteriovenous Graft ◽  
Vein Grafts ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Proliferation And Apoptosis ◽  
Autogenous Vein ◽  
Histological Characteristics ◽  
Underlying Mechanisms

Objectives. The aim of this study was to test the effects of collagen external scaffold (CES) in intimal hyperplasia of vein grafts and explore its underlying mechanisms. Methods. Thirty-six New Zealand white rabbits were randomized into no-graft group, graft group, and CES group. The rabbit arteriovenous graft model was established. In CES group, the vein graft was wrapped around with CES. The hemodynamic parameters of vein grafts were measured intraoperatively and 4 weeks after operation by ultrasonic examination. Histological characteristics of vein grafts were also evaluated 4 weeks later. The mRNA and protein levels of proliferating cell nuclear antigen (PCNA), active cleaved-caspase-3 (ClvCasp-3), and smooth muscle 22 alpha (SM22α) were measured 4 weeks later by quantitative real-time PCR and western blot. Results. CES significantly improved the hemodynamic stability of vein grafts, with higher blood velocity and blood flow. Similarly, CES also markedly mitigated intimal hyperplasia and inhibited dilatation of vein grafts. In CES group, the upexpression of PCNA and ClvCasp-3 and the downexpression of SM22α were inhibited. Conclusion. CES exerts beneficial effects in mitigating intimal hyperplasia and improving remodeling of autogenous vein grafts, which may be associated with reducing the proliferation and apoptosis and preserving the phenotype of VSMCs.

Beneficial effects of exercise training in heart failure are lost in male diabetic rats

2017 ◽  
Vol 123 (6) ◽  
pp. 1579-1591
Author(s):  
Dalila Boudia ◽  
Valérie Domergue ◽  
Philippe Mateo ◽  
Loubina Fazal ◽  
Mathilde Prud’homme ◽  
...  
Keyword(s):  
Heart Failure ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Cardiac Function ◽  
Diabetic Rats ◽  
Diabetic Patients ◽  
Coronary Artery Ligation ◽  
Standard Diet ◽  
Beneficial Effects ◽  
Patients With Heart Failure

Exercise training has been demonstrated to have beneficial effects in patients with heart failure (HF) or diabetes. However, it is unknown whether diabetic patients with HF will benefit from exercise training. Male Wistar rats were fed either a standard (Sham, n = 53) or high-fat, high-sucrose diet ( n = 66) for 6 mo. After 2 mo of diet, the rats were already diabetic. Rats were then randomly subjected to either myocardial infarction by coronary artery ligation (MI) or sham operation. Two months later, heart failure was documented by echocardiography and animals were randomly subjected to exercise training with treadmill for an additional 8 wk or remained sedentary. At the end, rats were euthanized and tissues were assayed by RT-PCR, immunoblotting, spectrophotometry, and immunohistology. MI induced a similar decrease in ejection fraction in diabetic and lean animals but a higher premature mortality in the diabetic group. Exercise for 8 wk resulted in a higher working power developed by MI animals with diabetes and improved glycaemia but not ejection fraction or pathological phenotype. In contrast, exercise improved the ejection fraction and increased adaptive hypertrophy after MI in the lean group. Trained diabetic rats with MI were nevertheless able to develop cardiomyocyte hypertrophy but without angiogenic responses. Exercise improved stress markers and cardiac energy metabolism in lean but not diabetic-MI rats. Hence, following HF, the benefits of exercise training on cardiac function are blunted in diabetic animals. In conclusion, exercise training only improved the myocardial profile of infarcted lean rats fed the standard diet. NEW & NOTEWORTHY Exercise training is beneficial in patients with heart failure (HF) or diabetes. However, less is known of the possible benefit of exercise training for HF patients with diabetes. Using a rat model where both diabetes and MI had been induced, we showed that 2 mo after MI, 8 wk of exercise training failed to improve cardiac function and metabolism in diabetic animals in contrast to lean animals.

scholarly journals Grape Seed Procyanidin B2 Protects Porcine Ovarian Granulosa Cells against Oxidative Stress-Induced Apoptosis by Upregulating let-7a Expression

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Jia-Qing Zhang ◽  
Xian-Wei Wang ◽  
Jun-Feng Chen ◽  
Qiao-Ling Ren ◽  
Jing Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Critical Role ◽  
Grape Seed ◽  
Luciferase Reporter ◽  
Tunel Staining ◽  
Protective Effects ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Oxidative stress is a causal factor and key promoter of all kinds of reproductive disorders related to granulosa cell (GC) apoptosis that acts by dysregulating the expression of related genes. Various studies have suggested that grape seed procyanidin B2 (GSPB2) may protect GCs from oxidative injury, though the underlying mechanisms are not fully understood. Therefore, whether the beneficial effects of GSPB2 are associated with microRNAs, which have been suggested to play a critical role in GC apoptosis by regulating the expression of protein-coding genes, was investigated in this study. The results showed that GSPB2 treatment protected GCs from a H2O2-induced apoptosis, as detected by an MTT assay and TUNEL staining, and increased let-7a expression in GCs. Furthermore, let-7a overexpression markedly increased cell viability and inhibited H2O2-induced GC apoptosis. Furthermore, the overexpression of let-7a reduced the upregulation of Fas expression in H2O2-treated GCs at the mRNA and protein levels. Dual-luciferase reporter assay results indicated that let-7a directly targets the Fas 3′-UTR. Furthermore, the overexpression of let-7a enhanced the protective effects of GSPB2 against GC apoptosis induced by H2O2. These results indicate that GSPB2 inhibits H2O2-induced apoptosis of GCs, possibly through the upregulation of let-7a.

Significance of changes in TNF-α and IL-10 levels in the progression of heart failure subsequent to myocardial infarction

2006 ◽  
Vol 291 (1) ◽  
pp. H106-H113 ◽  
Author(s):  
K. Kaur ◽  
A. K. Sharma ◽  
P. K. Singal
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Coronary Artery ◽  
Cardiac Function ◽  
Interleukin 10 ◽  
Mrna Levels ◽  
Protein Ratio ◽  
Protein Levels ◽  
Tnf Α ◽  
Membrane Bound

We tested whether a decrease in the ratio of interleukin-10 (IL-10) to tumor necrosis factor-α (TNF-α) correlates with the decrease in cardiac function in heart failure. It has been suggested that TNF-α plays a role in the progression of heart failure, and the effect of TNF-α in many tissues is modulated by IL-10. Any relation of these two cytokines to heart failure has never been examined. Cardiac function was assessed by echocardiographic and hemodynamic techniques in coronary artery-ligated rats at 1, 4, 8, and 16 wk after myocardial infarction (MI). Membrane-bound and soluble fractions of TNF-α and IL-10 proteins, the ratio of TNF-α to IL-10, and TNF-α and IL-10 mRNA levels were analyzed. Losartan was used to modify cardiac function in rats 4 wk after MI to further validate the relation between the IL-10-to-TNF-α ratio and cardiac function. Cardiac function deteriorated with time in all coronary artery-ligated groups, with severe failure at 16 wk after MI. Membrane-bound and soluble TNF-α protein fractions were increased 1 and 4 wk after MI, whereas TNF -α mRNA was increased 4 and 8 wk after MI. Membrane-bound IL-10 protein and mRNA levels were decreased 4, 8, and 16 wk after MI. The decrease in the IL-10-to-TNF-α protein ratio in all coronary artery-ligated groups correlated with the depressed cardiac function. Losartan improved cardiac function, membrane-bound and soluble TNF-α and IL-10 protein levels, the ratio of IL-10 to TNF-α, and IL-10 mRNA. This study suggests that a decrease in IL-10 and IL-10-to-TNF-α ratio correlates with depressed cardiac function.

scholarly journals Vitamin D signaling pathway plays an important role in the development of heart failure after myocardial infarction

2013 ◽  
Vol 114 (8) ◽  
pp. 979-987 ◽  
Author(s):  
Soochan Bae ◽  
Sylvia S. Singh ◽  
Hyeon Yu ◽  
Ji Yoo Lee ◽  
Byung Ryul Cho ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Vitamin D ◽  
Cardiac Function ◽  
Significant Decline ◽  
Vehicle Group ◽  
Wild Type ◽  
Protein Levels ◽  
Vitamin D Analog ◽  
Vitamin D Signaling

Accumulating evidence suggests that vitamin D deficiency plays a crucial role in heart failure. However, whether vitamin D signaling itself plays an important role in cardioprotection is poorly understood. In this study, we examined the mechanism of modulating vitamin D signaling on progression to heart failure after myocardial infarction (MI) in mice. Vitamin D signaling was activated by administration of paricalcitol (PC), an activated vitamin D analog. Wild-type (WT) mice underwent sham or MI surgery and then were treated with either vehicle or PC. Compared with vehicle group, PC attenuated development of heart failure after MI associated with decreases in biomarkers, apoptosis, inflammation, and fibrosis. There was also improvement of cardiac function with PC treatment after MI. Furthermore, vitamin D receptor (VDR) mRNA and protein levels were restored by PC treatment. Next, to explore whether defective vitamin D signaling exhibited deleterious responses after MI, WT and VDR knockout (KO) mice underwent sham or MI surgery and were analyzed 4 wk after MI. VDR KO mice displayed a significant decline in survival rate and cardiac function compared with WT mice after MI. VDR KO mice also demonstrated a significant increase in heart failure biomarkers, apoptosis, inflammation, and fibrosis. Vitamin D signaling promotes cardioprotection after MI through anti-inflammatory, antifibrotic and antiapoptotic mechanisms.

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