The histone 3 lysine 9 methyltransferase inhibitor chaetocin improves prognosis in a rat model of 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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Fetal programming effects of pentaerythritol tetranitrate in a rat model of superimposed preeclampsia

Journal of Molecular Medicine ◽

10.1007/s00109-020-01949-0 ◽

2020 ◽

Vol 98 (9) ◽

pp. 1287-1299

Author(s):

Andy W. C. Man ◽

Min Chen ◽

Yawen Zhou ◽

Zhixiong Wu ◽

Gisela Reifenberg ◽

...

Keyword(s):

Blood Pressure ◽

Glucose Tolerance ◽

Fetal Growth ◽

Rat Model ◽

High Salt ◽

Pentaerythritol Tetranitrate ◽

High Salt Diet ◽

Blood Pressure Elevation ◽

Salt Diet ◽

Normal Chow

Abstract Preeclampsia is a common medical condition during pregnancy and a major cause of maternal and prenatal mortality. The present study was conducted to investigate the effects of maternal treatment with pentaerythritol tetranitrate (PETN) in Dahl salt-sensitive rats (DSSR), a model of superimposed preeclampsia. F0 parental DSSR were treated with PETN (50 mg/kg) from the time point of mating to the end of lactation. Maternal PETN treatment improved fetal growth and had no effect on blood pressure in DSSR offspring fed with normal chow or high-salt diet. Upon high-fat diet (HFD) feeding, offspring from PETN-treated mother showed improved glucose tolerance despite similar weight gain. Unexpectedly, maternal PETN treatment significantly potentiated the HFD-induced blood pressure elevation in male DSSR offspring. Endothelium-derived hyperpolarization factor (EDHF)-mediated vasodilation was similar between NCD-fed and HFD-fed control offspring but was markedly reduced in HFD-fed PETN offspring. EDHF genes were downregulated in the vasculature of HFD-fed PETN offspring, which was associated with epigenetic changes in histone modifications. In conclusion, maternal PETN treatment in DSSR shows both beneficial and unfavorable effects. It improves fetal growth and ameliorates glucose tolerance in the offspring. Although maternal PETN treatment has no effect on blood pressure in offspring fed with normal chow or high-salt diet, the offspring is at higher risk to develop HFD-induced hypertension. PETN may potentiate the blood pressure response to HFD by epigenetic modifications of EDHF genes. Key messages The core findings of this article suggest that maternal PETN treatment of DSSR, a rat model of a spontaneous superimposed preeclampsia, leads to • Improvement of fetal growth; • No changes of maternal blood pressure or markers of preeclampsia; • Amelioration of HFD-induced glucose intolerance in adult offspring; • No changes in blood pressure development of the offspring on normal chow or high salt-diet; • Potentiation of blood pressure elevation of the offspring on HFD.

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High‐salt diet promotes crystal deposition through hypertension in Dahl salt‐sensitive rat model

International Journal of Urology ◽

10.1111/iju.14035 ◽

2019 ◽

Vol 26 (8) ◽

pp. 839-846 ◽

Cited By ~ 1

Author(s):

Yusuke Nakazawa ◽

Shinya Inoue ◽

Yuka Nakamura ◽

Yasuo Iida ◽

Yasuhito Ishigaki ◽

...

Keyword(s):

Rat Model ◽

High Salt ◽

Crystal Deposition ◽

High Salt Diet ◽

Salt Diet

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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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Abstract 500: The Cardiorenal Effects Of An Angiotensin Receptor Blocker (Valsartan) And Neprilysin Inhibitor (AHU377) Co-administered Daily For 6 Weeks In The Dahl Salt-sensitive Rat Model Of Volume-dependent Hypertension

Hypertension ◽

10.1161/hyp.64.suppl_1.500 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Alexander J McNamara ◽

Laxminarayan G Hegde ◽

Uwe Klein ◽

Craig Hill ◽

Cecile Yu ◽

...

Keyword(s):

Blood Pressure ◽

Body Weight ◽

Weight Gain ◽

Rat Model ◽

Renal Injury ◽

Body Weight Gain ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Neprilysin Inhibitor

The endogenous natriuretic peptide system helps maintain cardiovascular homeostasis by counterbalancing the deleterious effects of renin angiotensin system activation. This study examined whether the co-administration of an ARB (valsartan: VAL) with a NEPi (AHU377: AHU) can reduce cardiorenal disease progression in the Dahl salt-sensitive (Dahl/SS) rat model of volume-dependent hypertension. Methods: Studies were conducted in conscious Dahl/SS hypertensive rats that were maintained on a high salt diet and surgically implanted with telemetry transmitters for monitoring blood pressure. Rats were treated for 6 weeks with either vehicle, VAL (30 mg/kg, PO) or VAL+AHU (30 + 30 mg/kg, PO). Changes in cardiac and renal functions were measured via Left Ventricle (LV) pressure-volume loops and biomarkers (KIM-1, NGAL and osteopontin). Results: Dahl/SS rats maintained on a high salt diet exhibited a progressive decrease in body weight gain, progressive increases in blood pressure and elevation of plasma and urinary biomarkers indicative of cardiac stress or renal injury. VAL and VAL+AHU both improved body weight gain and blunted the progressive hypertension. However, the magnitude of the antihypertensive effect was greater for VAL+AHU (peak change: - 33 ± 3 mmHg) than for VAL alone (peak change: -15 ± 5 mmHg). VAL+AHU treatment provided greater renal protective effects, based on renal biomarkers KIM-1 (286 ± 29 vs. 341 ± 59 ng), NGAL (58 ±9 vs. 108 ± 28 μg) and osteopontin (1637 ± 372 vs 2155 ± 748 ng), than VAL alone. The VAL+AHU treatment group demonstrated a greater normalization in LV function, with improved systolic contractility over VAL alone (preload-adjusted PWR max = 1 ± 0.1 vs. 2 ± 0.5 μWatt/uL). Most notably, the VAL+AHU group exhibited a greater survival rate (94%: 15 of 16) than either the VAL (75%: 12 of 16) or vehicle (70%: 14 of 20) groups. Conclusion: In summary, chronic co-administration of an ARB and NEPi to Dahl/SS rats significantly attenuated progression of hypertension, suppressed increases in biomarkers indicative of renal injury, improved cardiac function and increased overall survival. These results suggest that co-administration of an ARB and NEPi may confer a beneficial therapeutic strategy for the treatment of cardiorenal disease.

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