Response of caspase-independent apoptotic factors to high salt diet-induced heart failure

To establish an experimental model for studying a specific transitional stage for compensatory hypertrophy to heart failure, we studied the pathophysiology of the left ventricle (LV) in Dahl salt-sensitive (DS) rats fed a high-salt diet. DS rats fed an 8% NaCl diet after the age of 6 wk developed concentric LV hypertrophy at 11 wk, followed by marked LV dilatation at 15-20 wk. During the latter stage, the DS rats showed labored respiration with LV global hypokinesis. All the DS rats died within 1 wk by massive pulmonary congestion. The dissected left ventricles revealed chamber dilatation and a marked increase in mass without myocardial necrosis. In contrast, corresponding Dahl salt-resistant (DR) rats fed the same diet showed neither mortality nor any of these pathological changes. The in vivo LV end-systolic pressure-volume relationship shifted to the right with a less steep slope in the failing DS rats compared with that in age-matched DR rats. Isometric contractions of LV papillary muscles isolated from these DS rats showed reduced tension development in the failing stage, but normal tension development in the hypertrophied stage. In conclusion, the DS rat fed a high-salt diet is a useful model showing rapidly developing congestive heart failure, in which the transition from compensatory hypertrophy to decompensatory dilatation of LV is easily and consistently manifested.

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Early Passive Leg Movement Prevents Against the Development of Heart Failure With Preserved Ejection Fraction in Rats

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.655009 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jian Liu ◽

Xi-xin Ji ◽

Yang Fu ◽

Wen-chao Zhang ◽

Hui-fang Ji ◽

...

Keyword(s):

Heart Failure ◽

Blood Vessel ◽

Signaling Pathway ◽

High Salt ◽

Preserved Ejection Fraction ◽

High Salt Diet ◽

Salt Diet ◽

Leg Movement ◽

Early Passive ◽

Tgf Β1

Exercising was reported by several studies to bring great benefits to heart failure with preserved ejection fraction (HFpEF), which reduced the hospitalization and the mortality of heart failure. However, the underlying mechanism of exercising on HFpEF remains unclear. In the present study, we designed and constructed a device that can perform early passive leg movement (ePLM) in rats and further observed whether treatment of ePLM exerts protective effects on HFpEF of rats. Rats were fed with high salt feed to establish an animal model of pre-clinical diastolic dysfunction (PDD), which would eventually develop into HFpEF, and then treated rats with ePLM. We conducted several experiments to evaluate the conditions of heart and blood vessel. The results show that diastolic functions of heart and blood vessel in rats were significantly improved by treatment of ePLM. We also found that pathological injuries of heart and blood vessel were ameliorated after treatment of ePLM. Moreover, treatment of ePLM decreased the protein levels of Collagen type I, Collagen type III, MMP2, and MMP9 in heart and blood vessel, indicating that cardiac and vascular fibrosis were reduced apparently by treatment of ePLM. Further investigation suggested that treatment of ePLM probably inhibit the activation of TGF-β1/Smad3 signaling pathway as well as promote the activation of Akt/eNOS signaling pathway in high salt diet induced HFpEF. In conclusion, treatment of ePLM alleviated high salt diet induced HFpEF by inhibiting fibrosis via suppressing TGF-β1/Smad3 signaling pathway as well as activating Akt/eNOS signaling pathway, implicating treatment of ePLM as a promising novel non-pharmacological approach for HFpEF.

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Alterations in apoptosis regulatory factors during hypertrophy and heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00556.2003 ◽

2004 ◽

Vol 287 (1) ◽

pp. H72-H80 ◽

Cited By ~ 48

Author(s):

Peter M. Kang ◽

Patrick Yue ◽

Zhilin Liu ◽

Oleg Tarnavski ◽

Natalya Bodyak ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Hypertrophy ◽

Primary Cultures ◽

High Salt ◽

Terminal Deoxynucleotidyl Transferase ◽

High Salt Diet ◽

Salt Diet ◽

Pathological Hypertrophy ◽

Increased Sensitivity ◽

Physiological Hypertrophy

Cardiac hypertrophy from pathological stimuli often proceeds to heart failure, whereas cardiac hypertrophy from physiological stimuli does not. In this study, physiological hypertrophy was created by a daily exercise regimen and pathological hypertrophy was created from a high-salt diet in Dahl salt-sensitive rats. The rats continued on a high-salt diet progressed to heart failure associated with an increased rate of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cardiomyocytes. We analyzed primary cultures of these hearts and found that only cardiomyocytes made hypertrophic by a pathological stimulus show increased sensitivity to apoptosis. Examination of the molecular changes associated with these distinct types of hypertrophy revealed changes in Bcl-2 family members and caspases favoring survival during physiological hypertrophy. However, in pathological hypertrophy, there were more diffuse proapoptotic changes, including changes in Fas, the Bcl-2 protein family, and caspases. Therefore, we speculate that this increased sensitivity to apoptotic stimulation along with proapoptotic changes in the apoptosis program may contribute to the development of heart failure seen in pathological cardiac hypertrophy.

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Sacubitril/Valsartan Reduces Fibrosis and Alleviates High-Salt Diet-Induced HFpEF in Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2020.600953 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wenchao Zhang ◽

Jianwei Liu ◽

Yang Fu ◽

Huifang Ji ◽

Zheyan Fang ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Signaling Pathway ◽

High Salt ◽

Angiotensin Receptor ◽

High Salt Diet ◽

Salt Diet ◽

Neprilysin Inhibitor ◽

Tgf Β1

Previous studies have confirmed the clinical efficacy of sacubitril/valsartan (Sac/Val) for the treatment of heart failure with reduced ejection fraction (HFrEF). However, the role of Sac/Val in heart failure with preserved ejection fraction (HFpEF) remains unclear. Sac/Val is a combination therapeutic medicine comprising sacubitril and valsartan that acts as a first angiotensin receptor blocker and neprilysin inhibitor (angiotensin-receptor neprilysin inhibitor (ARNI)). Here, we investigated the role of Sac/Val in high-salt diet-induced HFpEF coupled with vascular injury as well as the underlying mechanism. Rats were fed with high-salt feed, followed by intragastric administration of Sac/Val (68 mg/kg; i.g.). The results of functional tests revealed that a high-salt diet caused pathological injuries in the heart and vascular endothelium, which were significantly reversed by treatment with Sac/Val. Moreover, Sac/Val significantly decreased the levels of fibrotic factors, including type I collagen and type Ⅲ collagen, thus, reducing the ratio of MMP2/TIMP2 while increasing Smad7 levels. Further investigation suggested that Sac/Val probably reversed the effects of high-salt diet-induced HFpEF by inhibiting the activation of the TGF-β1/Smad3 signaling pathway. Thus, treatment with Sac/Val effectively alleviated the symptoms of high-salt diet-induced HFpEF, probably by inhibiting fibrosis via the TGF-β1/Smad3 signaling pathway, supporting the therapeutic potential of Sac/Val for the treatment of HFpEF.

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Abnormalities of sodium handling and of cardiovascular adaptations during high salt diet in patients with mild heart failure.

Circulation ◽

10.1161/01.cir.88.4.1620 ◽

1993 ◽

Vol 88 (4) ◽

pp. 1620-1627 ◽

Cited By ~ 74

Author(s):

M Volpe ◽

C Tritto ◽

N DeLuca ◽

S Rubattu ◽

M A Rao ◽

...

Keyword(s):

Heart Failure ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Mild Heart Failure ◽

Sodium Handling

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BALB/cJBom Treated with Angiotensin II and High Salt Diet Develop Pulmonary Hypertension and Right Sided Heart Failure while C57BL/6J Mice do not

The FASEB Journal ◽

10.1096/fasebj.2018.32.1_supplement.892.10 ◽

2018 ◽

Vol 32 (S1) ◽

Author(s):

Mediha Becirovic‐Agic ◽

Sofia Jönsson ◽

Maria K. Tveitarås ◽

Trude Skogstrand ◽

Tine V. Karlsen ◽

...

Keyword(s):

Heart Failure ◽

Pulmonary Hypertension ◽

Angiotensin Ii ◽

High Salt ◽

High Salt Diet ◽

Salt Diet

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The histone 3 lysine 9 methyltransferase inhibitor chaetocin improves prognosis in a rat model of high salt diet-induced heart failure

Scientific Reports ◽

10.1038/srep39752 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 15

Author(s):

Tomohiko Ono ◽

Naomi Kamimura ◽

Tomohiro Matsuhashi ◽

Toshihiro Nagai ◽

Takahiko Nishiyama ◽

...

Keyword(s):

Heart Failure ◽

Rat Model ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Histone 3

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Abstract 254: A Novel Mechanism for Aberrant Aldosterone Production in Heart Failure

Circulation Research ◽

10.1161/res.119.suppl_1.254 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Jin Endo ◽

Kaoru Yamashita ◽

Naohiro Yoshida ◽

Kentaro Ito ◽

Atsuhiro Ichihara ◽

...

Keyword(s):

Heart Failure ◽

Adrenal Gland ◽

Plasma Aldosterone ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Aldosterone Level ◽

Aldosterone Production ◽

H295r Cells ◽

Plasma Aldosterone Level

Objective: Aldosterone production by the adrenal gland is mainly regulated by the renin-angiotensin system (RAS), which is normally suppressed by a high-salt diet. However, plasma aldosterone levels are elevated in proportion to the severity of heart failure even if caused by high-salt intake. The inappropriate increase in plasma aldosterone level could not be diminished by pharmacological blockade of the RAS. We investigated the cellular mechanism underlying the aberrant aldosterone production in heart failure beyond the activation of RAS. Methods and Results: Dahl-salt sensitive rats fed high salt diet developed malignant hypertension, resulting in heart failure with increased plasma aldosterone level. The gene expression pattern of the adrenal gland from heart failure rats showed strikingly upregulated β3-adrenergic receptor (β3-AR) expression. Immunohistochemical staining confirmed that heart failure increased β3-AR expression in zona glomerulosa cells in adrenal gland of Dahl-salt sensitive rats. And the staining of pimonidazole, a hypoxia probe, revealed that the outer layer of adrenal cortex in the heart failure rat was under hypoxic condition. Hypoxia and DMOG, a chemical stabilizer of hypoxia-inducible factor, strongly induced β3-AR mRNA expression in H295R human adrenocortical carcinoma cells. Hypoxia-reoxygenation stimuli induced aldosterone production from H295R cells, which was blocked by SR59230A, a selective β3-AR antagonist, but not by losartan, an angiotensin II receptor blocker (ARB). Hypoxia endowed catecholamine responsiveness in H295R cells by increased β3-AR expression, wherein β3-AR agonist increased the phosphorylation levels of hormone-sensitive lipase (HSL) through activation of ERK pathway. Conclusions: In the present study, we demonstrated that the β3-AR induction in adrenal gland by hypoxia played an important role in aberrant aldosterone production in heart failure. The catecholamine stimuli through β3-AR in adrenocortical cells caused the ERK-mediated phosphorylation of HSL, suggesting that the HSL promotes lipolysis to supply substrates for the aldosterone biosynthesis.

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Spironolactone Preserves Cardiac Norepinephrine Reuptake in Salt-Sensitive Dahl Rats

Endocrinology ◽

10.1210/en.2005-1167 ◽

2006 ◽

Vol 147 (5) ◽

pp. 2526-2534 ◽

Cited By ~ 21

Author(s):

Sebastian J. Buss ◽

Johannes Backs ◽

Michael M. Kreusser ◽

Stefan E. Hardt ◽

Christiane Maser-Gluth ◽

...

Keyword(s):

Heart Failure ◽

Receptor Antagonist ◽

Ventricular Function ◽

Plasma Levels ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Endothelin 1 ◽

Endothelin A Receptor ◽

Endothelin A

An impairment of cardiac norepinephrine (NE) reuptake via the neuronal NE transporter (NET) enhances the effects of increased cardiac NE release in heart failure patients. Increasing evidence suggests that aldosterone and endothelins promote sympathetic overstimulation of failing hearts. Salt-sensitive Dahl rats (DS) fed a high-salt diet developed arterial hypertension and diastolic heart failure as well as elevated plasma levels of endothelin-1 and NE. Cardiac NE reuptake and NET-binding sites, as assessed by clearance of bolus-injected [3H]NE in isolated perfused rat hearts and [3H]mazindol binding, were reduced. Treatment of DS with the mineralocorticoid receptor antagonist spironolactone preserved the plasma levels of endothelin-1 and NE, cardiac NE reuptake, and myocardial NET density. Moreover, the ventricular function and survival of spironolactone-treated DS were significantly improved compared with untreated DS. The α1-inhibitor prazosin decreased blood pressure in DS similar to spironolactone treatment, but did not normalize the plasma levels of endothelin-1 and NE, NE reuptake, or ventricular function. In a heart failure-independent model, Wistar rats that were infused with aldosterone and fed a high-salt diet developed impaired cardiac NE reuptake. Treatment of these rats with the endothelin A receptor antagonist darusentan attenuated the impairment of NE reuptake. In conclusion, spironolactone preserves NET-dependent cardiac NE reuptake in salt-dependent heart failure. Evidence is provided that aldosterone inhibits NET function through an interaction with the endothelin system. Selective antagonism of the mineralocorticoid and/or the endothelin A receptor might represent therapeutic principles to prevent cardiac sympathetic overactivity in salt-dependent heart failure.

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Abstract 4394: Chronic Administration of Urocortin 2 Prevents the Development of Heart Failure in an Animal Model of Hypertensive Heart Disease

Circulation ◽

10.1161/circ.118.suppl_18.s_881 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Silvia Meili-Butz ◽

Marco Studer ◽

Dietlinde John ◽

Christian Morandi ◽

Matthias Pfisterer ◽

...

Keyword(s):

Heart Failure ◽

Blood Pressure ◽

Animal Model ◽

Body Weight ◽

Heart Disease ◽

Hypertensive Heart Disease ◽

Chronic Administration ◽

High Salt ◽

High Salt Diet ◽

Salt Diet

Background: Recently, novel corticotropin-releasing factor (CRF)-related peptides named Urocortin (Ucn) 1, 2, and 3 were described. Available data suggest that the Ucns are part of a peripheral CRF system modulating cardiovascular function and mediating cardiovascular responses to stress. Chronic Ucn2 administration induced sustained blood pressure lowering and prevented the development of left ventricular hypertrophy (LVH) in an animal model of hypertensive heart disease. However, no data are available whether chronic administration of Ucn2 may prevent the progression from LVH to heart failure. Methods: Experiments were performed in Dahl salt-sensitive rats. Animals were fed a high salt diet containing 4% NaCl to induce arterial hypertension, LVH, and heart failure. From the phase of LVH on (after 7 weeks of high salt diet), animals were injected with either Ucn2 at a dose of 2.5 μg/kg body weight or vehicle b.i.d. Animals underwent repetitive tail cuff blood pressure measurements and echocardiographic analysis of LV dimension and function at baseline (prior to first injection of Ucn2) and after 5 weeks of b.i.d. treatment with Ucn2. Results: Results are given in the following table as mean (± SD). No differences in heart weight/body weight ratios between Ucn2- and vehicle treated animals were found after 5 weeks of treatment. Conclusion: Chronic CRF receptor stimulation by Ucn2 in the severely hypertensive Dahl salt-sensitive rat, an animal model of hypertensive heart disease, prevents the progression from LVH to LV dilatation and the deterioration of LV function. Thus, chronic administration of Ucn2 might represent a novel approach to the prevention of heart failure.

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