scholarly journals GRKs and Epac1 Interaction in Cardiac Remodeling and Heart Failure

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 154
Author(s):  
Marion Laudette ◽  
Karina Formoso ◽  
Frank Lezoualc’h
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Physiological Regulation ◽  
Signaling Systems ◽  
Beneficial Effects ◽  
Sympathetic Overdrive ◽  
Β Adrenergic Receptors ◽  
G Protein Coupled ◽  
Stimulation Of

β-adrenergic receptors (β-ARs) play a major role in the physiological regulation of cardiac function through signaling routes tightly controlled by G protein-coupled receptor kinases (GRKs). Although the acute stimulation of β-ARs and the subsequent production of cyclic AMP (cAMP) have beneficial effects on cardiac function, chronic stimulation of β-ARs as observed under sympathetic overdrive promotes the development of pathological cardiac remodeling and heart failure (HF), a leading cause of mortality worldwide. This is accompanied by an alteration in cAMP compartmentalization and the activation of the exchange protein directly activated by cAMP 1 (Epac1) signaling. Among downstream signals of β-ARs, compelling evidence indicates that GRK2, GRK5, and Epac1 represent attractive therapeutic targets for cardiac disease. Here, we summarize the pathophysiological roles of GRK2, GRK5, and Epac1 in the heart. We focus on their signalosome and describe how under pathological settings, these proteins can cross-talk and are part of scaffolded nodal signaling systems that contribute to a decreased cardiac function and HF development.

scholarly journals Effects of Combination of ACE Inhibitor and Angiotensin Receptor Blocker on Cardiac Remodeling, Cardiac Function, and Survival in Rat Heart Failure

Circulation ◽  
2001 ◽  
Vol 103 (1) ◽  
pp. 148-154 ◽  
Author(s):  
Shokei Kim ◽  
Minoru Yoshiyama ◽  
Yasukatsu Izumi ◽  
Hitomi Kawano ◽  
Manabu Kimoto ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Rat Heart ◽  
Angiotensin Receptor Blocker ◽  
Ace Inhibitor ◽  
Receptor Blocker ◽  
Angiotensin Receptor

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 Qiliqiangxin Attenuates Cardiac Remodeling via Inhibition of TGF-β1/Smad3 and NF-κB Signaling Pathways in a Rat Model of Myocardial Infarction

2018 ◽  
Vol 45 (5) ◽  
pp. 1797-1806 ◽  
Author(s):  
Anbang Han ◽  
Yingdong Lu ◽  
Qi Zheng ◽  
Jian Zhang ◽  
YiZhou Zhao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Signaling Pathways ◽  
Rat Model ◽  
Cardiac Remodeling ◽  
Left Ventricular ◽  
Protective Effects ◽  
Tnf Α ◽  
Tgf Β1

Background/Aims: Qiliqiangxin (QL), a traditional Chinese medicine, has been demonstrated to be effective and safe for the treatment of chronic heart failure. Left ventricular (LV) remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after myocardial infarction (MI). Our previous studies have shown that QL exhibits cardiac protective effects against heart failure after MI. The objective of this study was to explore the effects of QL on myocardial fibrosis in rats with MI and to investigate the underlying mechanism of these effects. Methods: A rat model of acute myocardial infarction was induced by ligating the left anterior descending coronary artery. The rats were treated with QL (1.0 g/kg/day) for 4 weeks after surgery. Echocardiography and histology examination were performed to evaluate heart function and fibrosis, respectively. Protein levels of transforming growth factor-β1 (TGF-β1), phosphorylated Smad3 (p-Smad3), phosphorylated Smad7 (p-Smad7), collagen I (Col- I), alpha smooth muscle actin (a-SMA), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), nuclear factor κB (NF-κB), and phosphorylated inhibitor of kappa B alpha (p-IκBα) were measured by western blot analysis. Results: QL treatment ameliorated adverse cardiac remodeling 8 weeks after AMI, including better preservation of cardiac function, decreased inflammation, and reduced fibrosis. In addition, QL treatment reduced Col-I, a-SMA, TGF-β1, and p-Smad3 expression levels but increased p-Smad7 levels in postmyocardial infarct rat hearts. QL administration also reduced the elevated levels of cardiac inflammation mediators, such as TNF-α and IL-6, as well as NF-κB and p-IκBα expression. Conclusions: QL therapy exerted protective effects against cardiac remodeling potentially by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways, thereby preserving cardiac function, as well as reducing myocardial inflammation and fibrosis.

scholarly journals Nitric oxide — soluble guanylate cyclase — cyclic guanosine monophosphate signaling pathway in the pathogenesis of heart failure and search for novel therapeutic targets

2021 ◽  
Vol 20 (6) ◽  
pp. 3035
Author(s):  
Zh. D. Kobalava ◽  
P. V. Lazarev
Keyword(s):  
Heart Failure ◽  
Signaling Pathway ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Severe Disease ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Phase Iii ◽  
Beneficial Effects ◽  
Stimulation Of

Heart failure is a severe disease with an unfavorable prognosis, which requires intensification of therapy and the search for novel approaches to treatment. In this review, the physiological significance of soluble guanylate cyclase-related signaling pathway, reasons for decrease in its activity in heart failure and possible consequences are discussed. Pharmacological methods of stimulating the production of cyclic guanosine monophosphate using drugs with different mechanisms of action are considered. Data from clinical studies regarding their effectiveness and safety are presented. A promising approach is stimulation of soluble guanylate cyclase, which showed beneficial effects in preclinical studies, as well as in the recently completed phase III VICTORIA study.

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.

Abstract 211: Intercellular Adhesion Molecule 1 Regulates Cardiac Remodeling and Function and T Cell Recruitment to the Heart in Pressure Overload Induced Heart Failure

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Ane Miren Salvador ◽  
Tania Nevers ◽  
Mark Aronovitz ◽  
Robert Blanton ◽  
Pilar Alcaide
Keyword(s):  
Heart Failure ◽  
T Cell ◽  
Cardiac Function ◽  
Adhesion Molecule ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
Leukocyte Recruitment ◽  
Cell Infiltration ◽  
Cell Recruitment ◽  
T Cell Infiltration

Background: Left ventricular (LV) dysfunction and Heart Failure (HF) are associated in humans with systemic inflammation, including increased circulating levels of pro-inflammatory cytokines and soluble intercellular cell adhesion molecule-1 (ICAM-1). Endothelial ICAM-1 regulates leukocyte recruitment into tissues, which in the heart can result in altered cardiac function. We hypothesize that ICAM-1 regulates cardiac remodeling by mediating leukocyte recruitment to the LV and thus contributing to worsening of cardiac function during pressure overload induced HF. Methods and results: We used the mouse model of Thoracic Aortic Constriction (TAC) to induce LV remodeling and HF in WT and ICAM-1 deficient mice (ICAM-1 -/- ). Immunohistochemistry, flow cytometry, qPCR, echocardiography and hemodynamics were used to investigate leukocyte infiltration into the LV, cardiac function, hypertrophy and fibrosis mechanisms taking place in response to TAC. Endothelial ICAM-1 was upregulated in WT mice in response to TAC as compared to Sham, correlating with LV T cell infiltration. In contrast, CD3+ and CD4+ T cell recruitment into the LV was significantly reduced in response to TAC in ICAM-1 -/- mice as compared to WT mice. Further, indices of sistolic and diastolic function were preserved in ICAM-1 -/- mice (dP/dt max = WT TAC 5,627±549 vs. ICAM-1 -/- TAC 8,396±1,495 ; dP/dt min = WT TAC -5,614±1,195 vs. ICAM- 1-/- TAC -8,832±2,274) and the End Diastolic Pressure was significantly lower than in WT TAC mice (31.0±7.0mmHg in WT TAC vs 8.1±7.8mmHg in ICAM-1 -/- TAC). Despite increased LV weight, ICAM-1 -/- did not develop fibrosis in response to TAC, with blunted collagen deposition and lack of mRNA upregulation of fibrotic markers Collagen-I, TGFβ and SMAα four and ten weeks after TAC when dilated cardiomiopathy is established in WT mice. Conclusion: Our data indicate that ICAM-1 regulates LV T cell infiltration, cardiac function and fibrosis in HF induced by TAC. Further studies will determine whether ICAM-1 contributes to HF pathogenesis exclusively by regulating T cell interactions with the LV endothelium or participating in novel mechanisms regulating cardiac cell function, which could represent new targets for the treatment of this deadly syndrome.

Myocardial tumor necrosis factor-α secretion in hypertensive and heart failure-prone rats

1999 ◽  
Vol 277 (2) ◽  
pp. H543-H550 ◽  
Author(s):  
Marina R. Bergman ◽  
Ruey H. Kao ◽  
Sylvia A. McCune ◽  
Bethany J. Holycross
Keyword(s):  
Heart Failure ◽  
Tumor Necrosis Factor ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Tumor Necrosis ◽  
Left Ventricular ◽  
Sprague Dawley ◽  
Spontaneously Hypertensive ◽  
Tnf Α ◽  
Necrosis Factor

Acute increases in blood pressure (BP) increase myocardial tumor necrosis factor (TNF)-α production, but it is not known whether chronic hypertensive stress elevates myocardial TNF-α production, possibly contributing to cardiac remodeling, decreased cardiac function, and faster progression to heart failure. BP, cardiac function, and size were evaluated in normotensive [Sprague-Dawley (SD)], spontaneously hypertensive (SHR), and spontaneously hypertensive heart failure-prone (SHHF) rats at 6, 12, 15, and 18 mo of age and in failing SHHF. Left ventricular tissues were evaluated for secretion of bioactive TNF-α and inhibition of TNF-α secretion by phosphodiesterase inhibitors. All ventricles secreted bioactive and immunoreactive TNF-α, but secretion decreased with age. SHR and SHHF rats secreted more TNF-α than SD rats at 6 mo of age, but only failing SHHF rats secreted significantly more TNF-α at 18 mo. Amrinone inhibited TNF-α secretion in all rats and was less potent but more efficacious than RO-201724 in all strains. TNF-α secretion correlated with BP and left ventricular mass in 6-mo-old rats, but this relationship disappeared with age. Results suggest that hypertension and/or cardiac remodeling is associated with elevated myocardial TNF-α, and, although hypertension, per se, did not maintain elevated cardiac TNF-α levels, SHHF rats increase TNF-α production during the end stages of failure.

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