Evaluation of cardiac hypertrophy in spontaneous hypertensive rats using measures of left ventricular deformation and LVEF of cardiac microPET imaging data*1

Peak left ventricular (LV) function, during rapid volume expansion, and cardiocyte structure were studied in rats with developing cardiac hypertrophy in response to Grollman hypertension (1 kidney, 1 figure 8) after chemical sympathectomy with 6-hydroxydopamine. This form of renovascular hypertension led to the same magnitude of hypertrophy in rats with or without sympathectomy. Indices of peak LV function, measured during acute volume expansion, tended to be normal or slightly higher in hypertensive rats than in controls. Sympathectomy in rats with hypertension significantly improved cardiac and stroke indices while decreasing total peripheral resistance at peak cardiac output. Despite similar magnitudes of LV hypertrophy (LVH) in the two hypertensive groups, cardiocytes in sympathectomized rats had higher mitochondrial volume densities and slightly lower myofibrillar volume densities. After regional sympathectomy of the anterior portion of the LV with phenol, mitochondrial volume density increased by 21% in hypertensive rats with LVH. These data indicate that, during the development of LVH in response to renovascular hypertension, sympathetic nerves do not contribute to the magnitude of LVH but may limit improvement in peak LV performance in response to increased preload. However, sympathetic nerves do play a role in the regulation of mitochondrial and myofibril growth.

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A Reduction in ADAM17 Expression Is Involved in the Protective Effect of the PPAR-α Activator Fenofibrate on Pressure Overload-Induced Cardiac Hypertrophy

PPAR Research ◽

10.1155/2018/7916953 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Si-Yu Zeng ◽

Hui-Qin Lu ◽

Qiu-Jiang Yan ◽

Jian Zou

Keyword(s):

Body Weight ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Wall Thickness ◽

Protective Action ◽

Pressure Overload ◽

Left Ventricular ◽

Heart Weight ◽

Hypertensive Rats ◽

Protein Levels

The peroxisome proliferator-activated receptor-α (PPAR-α) agonist fenofibrate ameliorates cardiac hypertrophy; however, its mechanism of action has not been completely determined. Our previous study indicated that a disintegrin and metalloproteinase-17 (ADAM17) is required for angiotensin II-induced cardiac hypertrophy. This study aimed to determine whether ADAM17 is involved in the protective action of fenofibrate against cardiac hypertrophy. Abdominal artery constriction- (AAC-) induced hypertensive rats were used to observe the effects of fenofibrate on cardiac hypertrophy and ADAM17 expression. Primary cardiomyocytes were pretreated with fenofibrate (10 μM) for 1 hour before being stimulated with angiotensin II (100 nM) for another 24 hours. Fenofibrate reduced the ratios of left ventricular weight to body weight (LVW/BW) and heart weight to body weight (HW/BW), left ventricular anterior wall thickness (LVAW), left ventricular posterior wall thickness (LVPW), and ADAM17 mRNA and protein levels in left ventricle in AAC-induced hypertensive rats. Similarly, in vitro experiments showed that fenofibrate significantly attenuated angiotensin II-induced cardiac hypertrophy and diminished ADAM17 mRNA and protein levels in primary cardiomyocytes stimulated with angiotensin II. In summary, a reduction in ADAM17 expression is associated with the protective action of PPAR-α agonists against pressure overload-induced cardiac hypertrophy.

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The Effects of Aqueous Extract from Nardostachys chinensis Batalin on Blood Pressure and Cardiac Hypertrophy in Two-Kidney One-Clip Hypertensive Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/4031950 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Rayile Aisa ◽

Zhaoxia Yu ◽

Xiangyang Zhang ◽

Dilinuer Maimaitiyiming ◽

Lipeng Huang ◽

...

Keyword(s):

Blood Pressure ◽

Cardiac Hypertrophy ◽

Aqueous Extract ◽

Caspase 3 ◽

Left Ventricular ◽

Left Renal Artery ◽

Hypertensive Rats ◽

Left Ventricular Tissue ◽

Nardostachys Chinensis ◽

Ventricular Tissue

Aims. The aim of this study was to investigate the effects of the aqueous extract of Nardostachys chinensis Batalin (NCBAE) on blood pressure and cardiac hypertrophy using two-kidney one-clip (2K1C) hypertensive rats. Methods. 2K1C rat models were set up by clipping the left renal artery. Sham-operated rats underwent the same surgical procedure except for renal arterial clipping. 2K1C hypertensive rats were orally given NCBAE at doses of 210, 420, and 630 mg·kg−1·d−1 for 6 weeks. Twelve weeks after surgery, rat SBP and echocardiographic parameters were measured, cardiac histopathology was assessed, serum NO and LDH were detected, and the expression of Bcl-2 and caspase-3 of left ventricular tissue was assessed by western blot. Results. Treatment with NCBAE resulted in a decrease of SBP, LVPWd, LVPWs, IVSd, IVSs, LVW/BW ratio, and cardiomyocyte CSA, an increase of LVEF, and inhibition of 2K1C-induced reduction in serum NO and elevation of LDH compared with 2K1C group. NCBAE intervention also showed a significant increase of Bcl-2 expression and reduction of cleaved caspase-3 level dose-dependently in left ventricular tissue. Conclusion. Our data demonstrate that NCBAE has an antihypertensive property and protective effect on 2K1C-induced cardiac hypertrophy especially at the dose of 630 mg·kg−1·d−1.

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Dyrk1A-ASF-CaMKIIδ Signaling Is Involved in Valsartan Inhibition of Cardiac Hypertrophy in Renovascular Hypertensive Rats

Cardiology ◽

10.1159/000441695 ◽

2015 ◽

Vol 133 (3) ◽

pp. 198-204 ◽

Cited By ~ 3

Author(s):

Jian Yao ◽

Xiaotong Qin ◽

Jianhua Zhu ◽

Hongzhuan Sheng

Keyword(s):

Alternative Splicing ◽

Cardiac Hypertrophy ◽

Protein Expression ◽

Mrna Expression ◽

Systolic Function ◽

Left Ventricular ◽

Parameter Analysis ◽

Hypertensive Rats ◽

Dual Specificity ◽

Dependent Protein

Objectives: It is known that the expression, activity and alternative splicing of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) are dysregulated in the cardiac remodeling process. Recently, we found a further signaling pathway, by which dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) regulates the alternative splicing of CaMKIIδ via the alternative splicing factor (ASF), i.e. Dyrk1A-ASF-CaMKIIδ. In this study, we aimed to investigate whether Dyrk1A-ASF-CaMKIIδ signaling was involved in valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats. Methods: Rats were subjected to two kidney-one clip (2K1C) surgery and then treated with valsartan (30 mg/kg/day) for 8 weeks. Hypertrophic parameter analysis was then performed. Western blot analysis was used to determine the protein expression of Dyrk1A and ASF and RT-PCR was used to analyze the alternative splicing of CaMKIIδ in the left ventricular (LV) sample. Results: Valsartan attenuated cardiac hypertrophy in 2K1C rats but without impairment of cardiac systolic function. Increased protein expression of Dyrk1A and decreased protein expression of ASF were observed in the LV sample of 2K1C rats. Treatment of 2K1C rats with valsartan reversed the changes in Dyrk1A and ASF expression in the LV sample. Valsartan adjusted the 2K1C-induced imbalance in alternative splicing of CaMKIIδ by upregulating the mRNA expression of CaMKIIδC and downregulating the mRNA expression of CaMKIIδA and CaMKIIδB. Conclusions: Valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats was mediated, at least partly, by Dyrk1A-ASF-CaMKIIδ signaling.

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Repetitive hyperthermia attenuates progression of left ventricular hypertrophy and increases telomerase activity in hypertensive rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00225.2011 ◽

2012 ◽

Vol 302 (10) ◽

pp. H2092-H2101 ◽

Cited By ~ 10

Author(s):

Jun-ichi Oyama ◽

Toyoki Maeda ◽

Makoto Sasaki ◽

Yoshihiro Higuchi ◽

Koichi Node ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Telomerase Activity ◽

Hsp90 Inhibitor ◽

Left Ventricular ◽

High Salt ◽

Hypertensive Rats ◽

High Salt Diet ◽

Blood Pressure Elevation ◽

Salt Diet ◽

Group A

We investigated the hypothesis that repetitive hyperthermia (RHT) attenuates the progression of cardiac hypertrophy and delays the transition from hypertensive cardiomyopathy to heart failure in Dahl salt-sensitive (DS) hypertensive rats. Six-week-old DS rats were divided into the following five groups: a normal-salt diet (0.4% NaCl) (NS group), a normal-salt diet plus RHT by daily immersion for 10 min in 40°C water (NS+RHT group), a high-salt diet (8% NaCl) (HS group), a high-salt diet (8% NaCl) plus RHT (HS+RHT group), and high-salt diet (8% NaCl) plus RHT with 17-DMAG (HSP90 inhibitor) administration (HS+RHT+17-DMAG group). All rats were killed at 10 wk. Cardiac hypertrophy and fibrosis were noted in the HS group, whereas RHT attenuated salt-induced cardiac hypertrophy, myocardial and perivascular fibrosis, and blood pressure elevation. The phosphorylated endothelial nitric oxide synthase (eNOS) and Akt were decreased in the HS group compared with the NS group, but these changes were not observed in the HS+RHT group. The levels of HSP60, 70, and 90 were elevated by RHT. Moreover, the increased levels of iNOS, nitrotyrosine, Toll-like receptor-4, BNP, PTX3, and TBARS in the HS group were inhibited by RHT. Telomeric DNA length, telomerase activity, and telomere reverse transcriptase (TERT) were reduced in the HS group; however, these changes were partially prevented by hyperthermia. In conclusion, RHT attenuates the development of cardiac hypertrophy and fibrosis and preserves telomerase, TERT activity and the length of telomere DNA in salt-induced hypertensive rats through activation of eNOS and induction of HSPs.

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Small-conductance Ca2+-activated K+ current is upregulated via the phosphorylation of CaMKII in cardiac hypertrophy from spontaneously hypertensive rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00825.2014 ◽

2015 ◽

Vol 309 (6) ◽

pp. H1066-H1074 ◽

Cited By ~ 11

Author(s):

Kazuya Mizukami ◽

Hisashi Yokoshiki ◽

Hirofumi Mitsuyama ◽

Masaya Watanabe ◽

Taro Tenma ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Ventricular Arrhythmias ◽

Left Ventricular ◽

Protein Isoforms ◽

Sk Channels ◽

Hypertensive Rats ◽

Wky Rats ◽

Sk Channel ◽

Increased Risk ◽

Small Conductance

Left ventricular hypertrophy is associated with an increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca2+-activated K+ (SK) channels are involved in the pathogenesis of ventricular arrhythmias in heart failure. The present study aimed to test the hypothesis that SK channel activity is increased via the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway in hypertensive cardiac hypertrophy. Normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) were used. Whole cell membrane currents were recorded in isolated ventricular myocytes by the patch-clamp method, and apamin-sensitive K+ current ( IKAS), which is inhibited by apamin (100 nM), an SK channel blocker, was evaluated. IKAS at 40 mV was present in SHRs, whereas it was hardly detectable in WKY rats (0.579 ± 0.046 vs. 0.022 ± 0.062 pA/pF, both n = 6, P < 0.05). IKAS was almost completely abolished by 1 μM KN-93, a CaMKII inhibitor, in SHRs. Optical recordings of left ventricular anterior wall action potentials revealed that apamin prolonged the late phase of repolarization only in SHRs. Western blot analysis of SK channel protein isoforms demonstrated that SK2 was significantly increased in SHRs compared with WKY rats (SK2/GAPDH: 0.66 ± 0.07 vs. 0.40 ± 0.02, both n = 6, P < 0.05), whereas SK1 and SK3 did not differ between groups. In addition, autophosphorylated CaMKII was significantly increased in SHRs (phosphorylated CaMKII/GAPDH: 0.80 ± 0.06 vs. 0.58 ± 0.06, both n = 6, P < 0.05) despite a comparable total amount of CaMKII between groups. In conclusion, SK channels are upregulated via the enhanced activation of CaMKII in cardiac hypertrophy in SHRs.

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Effect of pravastatin on development of left ventricular hypertrophy in spontaneously hypertensive rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00417.2004 ◽

2005 ◽

Vol 289 (1) ◽

pp. H220-H227 ◽

Cited By ~ 17

Author(s):

Tsung-Ming Lee ◽

Mei-Shu Lin ◽

Tsai-Fwu Chou ◽

Chang-Her Tsai ◽

Nen-Chung Chang

Keyword(s):

Body Weight ◽

Cardiac Hypertrophy ◽

Left Ventricular Mass ◽

Spontaneously Hypertensive Rats ◽

Ventricular Hypertrophy ◽

Left Ventricular Mass Index ◽

Left Ventricular ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Ventricular Mass Index

Endothelin (ET)-1 has been implicated in the development of cardiac hypertrophy. We investigated the effect of pravastatin on development of ventricular hypertrophy in spontaneously hypertensive rats (SHR) and whether the attenuated hypertrophic effect was via reduced ET-1 expression. Normolipidemic SHR were treated with one of the following therapies for 8 wk: vehicle, the nonselective ET receptor antagonists bosentan, pravastatin, mevalonate, hydralazine, or combination of pravastatin + mevalonate from the age of 8 wk at the very early stage of cardiac hypertrophy. Treatment with bosentan and pravastatin significantly decreased left ventricular mass index for body weight and cardiomyocyte sizes isolated by enzymatic dissociation. The myocardial ET-1 levels and preproET-1 mRNA assessed using real-time quantitative RT-PCR were significantly higher (both P < 0.001) in the SHR compared with Wistar-Kyoto rats. The increased tissue ET-1 levels can be inhibited after pravastatin administration. Immunohistochemical analysis confirmed the changes of ET-1. Left ventricular mass index for body weight correlated positively with tissue ET-1 levels ( P = 0.0004). A dissociation between the effects of blood pressure and cardiac structure was noted, because pravastatin and hydralazine reduced arterial pressure similarly. Pravastatin-induced effects were reversed by the addition of mevalonate. In conclusion, these results suggest a crucial role of cardiac endothelin system in the early development of ventricular hypertrophy in the SHR. Pravastatin is endowed with cardiac antihypertropic properties that are independent of its hemodynamic and hypolipidemic effects and appear to be related to their capacity to decrease cardiac ET-1 levels, which is linked to mevalonate metabolism.

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Abstract 059: N-acylhydrazone Derivative Improves Cardiac Hypertrophy and Dysfunction in Spontaneously Hypertensive Rats Submitted to Myocardial Infarction

Circulation Research ◽

10.1161/res.113.suppl_1.a059 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Gisele Zapata-Sudo ◽

Jaqueline S Silva ◽

Sharlene L Pereira ◽

Rodolfo C Maia ◽

Carlos A Fraga ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Hypertrophy ◽

Spontaneously Hypertensive Rats ◽

Ventricular Dysfunction ◽

Volume Fraction ◽

Systolic Pressure ◽

Left Ventricular ◽

Heart Weight ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

Aims: Ventricular dysfunction is observed in arterial hypertension and myocardial infarction (MI). The N -acylhydrazone derivative, 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294), which has been described as a potent cardiac inotropic agent with vasodilator properties, was orally administrated in spontaneously hypertensive rats (SHR) submitted to experimental MI. Methods and Results: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. Male SHR (12 - 14 week-old) were randomly divided in sham-operated (SHAM) and infarcted groups (MI) and were treated or not with LASSBio-294 (20 mg/kg p.o.) during 8 weeks. Under sevoflurane anesthesia, the animals were submitted to a ligature of the anterior descending coronary artery to produce the MI. After 8 weeks, rats were submitted to treadmill test and also, the following hemodynamic parameters were analyzed: left ventricular end diastolic pressure (LVEDP), left ventricular end-systolic pressure (LVESP) and LV contractility (dp/dt max ). Hypertrophy was measured using the relation between heart weight to body weight (heart/BW). The volume fraction of collagen (%) was determined by measuring the area of stained tissue within a given field by picrosirius red staining. The results are presented in the following table. Conclusions: Treatment of infarcted SHR with LASSBio-294 reduced intolerance to exercise, ventricular dysfunction, cardiac hypertrophy and fibrosis.

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MiR-139-3p is related to left ventricular hypertrophy and cardiomyocyte apoptosis in two-kidney one-clip hypertensive rats

Archives of Biological Sciences ◽

10.2298/abs140820008y ◽

2015 ◽

Vol 67 (2) ◽

pp. 427-435

Author(s):

Xiaomin Yang ◽

Hui Yu ◽

Hai Hu ◽

Jianwei Yue ◽

Xuyang Tian ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Ventricular Hypertrophy ◽

Ventricular Myocardium ◽

Left Ventricular ◽

Cardiomyocyte Apoptosis ◽

Mitogen Activated Protein Kinase ◽

Left Ventricular Myocardium ◽

Hypertensive Rats ◽

Mitogen Activated Protein

MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression in many physiological and pathological processes. Previous studies have reported the role of miR-139-3p in cancer. However, its specific roles and functions in the heart undergoing hypertrophy have yet to be fully elucidated. In the present study, a significant upregulation of miR-139-3p expression was demonstrated in the left ventricular myocardium of two-kidney one-clip (2K1C) hypertensive rats using microarray and quantitative real-time PCR (qRT-PCR). Based on computational analysis, we observed that miR-139-3p can control the expression of mitogen-activated protein kinase 1 (MAPK1) as a target gene, which is essential for the induction of cardiac hypertrophy and cardiomyocyte apoptosis. This study provides first information that the highly expressed miR-139-3p might be closely involved in MAPK1-mediated cardiac hypertrophy and cardiomyocyte apoptotic processes in 2K1C rat.

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