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

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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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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GW25-e5146 High-salt diet decreases ACE2 and activates TGF-β1/Smads signaling pathway in vascular remodeling

Journal of the American College of Cardiology ◽

10.1016/j.jacc.2014.06.1108 ◽

2014 ◽

Vol 64 (16) ◽

pp. C238

Author(s):

Liu Chan ◽

Shang Qian-Hui

Keyword(s):

Signaling Pathway ◽

Vascular Remodeling ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Tgf Β1

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Transition from compensatory hypertrophy to dilated, failing left ventricles in Dahl salt-sensitive rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.267.6.h2471 ◽

1994 ◽

Vol 267 (6) ◽

pp. H2471-H2482 ◽

Cited By ~ 26

Author(s):

M. Inoko ◽

Y. Kihara ◽

I. Morii ◽

H. Fujiwara ◽

S. Sasayama

Keyword(s):

Heart Failure ◽

Systolic Pressure ◽

Myocardial Necrosis ◽

Compensatory Hypertrophy ◽

High Salt ◽

High Salt Diet ◽

Tension Development ◽

Salt Diet ◽

The Right

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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A6369 TRPV1 Activation Attenuates High-Salt Diet-Induced Vascular Fibrosis Via Inhibition Of TGF-β1 Signaling

Journal of Hypertension ◽

10.1097/01.hjh.0000548089.52976.0d ◽

2018 ◽

Vol 36 ◽

pp. e25-e26

Author(s):

Liu Chan ◽

Shang Qian-Hui

Keyword(s):

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Tgf Β1

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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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Curcumin, an Inhibitor of p300-HAT Activity, Suppresses the Development of Hypertension-Induced Left Ventricular Hypertrophy with Preserved Ejection Fraction in Dahl Rats

Nutrients ◽

10.3390/nu13082608 ◽

2021 ◽

Vol 13 (8) ◽

pp. 2608

Author(s):

Yoichi Sunagawa ◽

Masafumi Funamoto ◽

Kana Shimizu ◽

Satoshi Shimizu ◽

Nurmila Sari ◽

...

Keyword(s):

Left Ventricular Hypertrophy ◽

Ejection Fraction ◽

Ventricular Hypertrophy ◽

Systolic Function ◽

Left Ventricular ◽

High Salt ◽

Preserved Ejection Fraction ◽

High Salt Diet ◽

Salt Diet ◽

Hat Inhibitor

We found that curcumin, a p300 histone acetyltransferase (HAT) inhibitor, prevents cardiac hypertrophy and systolic dysfunction at the stage of chronic heart failure in Dahl salt-sensitive rats (DS). It is unclear whether curcumin suppresses the development of hypertension-induced left ventricular hypertrophy (LVH) with a preserved ejection fraction. Therefore, in this study, we randomized DS (n = 16) and Dahl salt-resistant (DR) rats (n = 10) at 6 weeks of age to either curcumin or vehicle groups. These rats were fed a high-salt diet and orally administrated with 50 mg/kg/d curcumin or its vehicle for 6 weeks. Both curcumin and vehicle treatment groups exhibited similar degrees of high-salt diet-induced hypertension in DS rats. Curcumin significantly decreased hypertension-induced increase in posterior wall thickness and LV mass index, without affecting the systolic function. It also significantly reduced hypertension-induced increases in myocardial cell diameter, perivascular fibrosis and transcriptions of the hypertrophy-response gene. Moreover, it significantly attenuated the acetylation levels of GATA4 in the hearts of DS rats. A p300 HAT inhibitor, curcumin, suppresses the development of hypertension-induced LVH, without affecting blood pressure and systolic function. Therefore, curcumin may be used for the prevention of development of LVH in patients with hypertension.

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