Atorvastatin reverses cardiac remodeling possibly through regulation of Protein Kinase D/Myocyte Enhancer Factor 2D activation in spontaneously hypertensive rats

Geng, Jing; Zhao, Zhuo; Kang, Wenyan; Wang, Wei; Zhang, Yun; Gao, Zhiming

doi:10.1016/j.phrs.2009.08.004

Cited by 21 publications

(23 citation statements)

References 35 publications

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“…Heart rate among SHR groups and WKY rats was not different (Table 1). Consistent with our previous study, 28 systolic BP was significantly elevated in SHRs compared with WKY rats of the same age. In SHR group, both systolic BP and heart weight increased during aging, while WKY rats remained unchanged.…”

Section: Resultssupporting

confidence: 92%

“…Consistent with our previous studies, 28 ATO showed protective effects on cardiac remodeling. Compared with WKY rats, vehicle-treated SHRs showed increased LV mass, LV wall thickness, interventricular septal diameter and LV posterior wall at diastole (Table 2 and Figure 1a).…”

Section: Effects Of Ato On Cardiac Remodeling Of Shrssupporting

confidence: 93%

“…This hypertrophic phenotype was most pronounced in the 12-month-old SHRs. Although it is controversial regarding the effects of statin in attenuating cardiac function and improving survival rate in HF, [18][19][20]28 the present study has shown that chronic ATO, at the dose of 50 mg kg − 1 per day, attenuated cardiac remodeling in SHR. This result is consistent with our previous report, and that of others, using the same dose of ATO.…”

Section: Discussionmentioning

confidence: 47%

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Augmentation of autophagy by atorvastatin via Akt/mTOR pathway in spontaneously hypertensive rats

Wang

Qian

et al. 2015

Hypertens Res

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Autophagy is activated in hypertension-induced cardiac hypertrophy. However, the mechanisms and significance of an activated autophagy are not clear. This study was designed to determine the role of atorvastatin (ATO) in cardiac autophagy and associated benefits on cardiac remodeling and left ventricular function in spontaneously hypertensive rats (SHRs). Twenty-eight male SHRs at 8 weeks of age were randomized to treatment with vehicle (saline solution; SHR+V) or ATO (SHR+ATO; 50 mg kg(-1) per day) for 6 or 12 months. Age-matched male Wistar-Kyoto (WKY) rats were used as normotensive controls. Cardiac magnetic resonance was used to evaluate cardiac function and structure. Compared with WKY rats, SHRs showed significant left ventricle (LV) dysfunction, remodeling and increases in cardiomyocyte size, which were all attenuated by 6 and 12 months of ATO treatment. Compared with WKY rats, autophagy was activated in the hearts of SHRs and this effect was amplified by chronic ATO treatment, particularly following 12 months of treatment. Protein expression levels of microtubule-associated protein-1 light chain 3-II and beclin-1, the biomarkers of an activated cardiac autophagy, were significantly elevated in ATO-treated versus vehicle-treated SHRs and control WKY rats. Cardiac Akt and phosphorylated mammalian target of rapamycin (mTOR) expression were also increased in the hearts of SHR versus WKY rats, and this effect was attenuated by ATO treatment. These findings suggest that ATO-mediated improvements in LV function and structure in SHRs may be, in part, through its regulation of cardiac autophagy via the Akt/mTOR pathway.

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Section: Resultssupporting

confidence: 92%

Section: Effects Of Ato On Cardiac Remodeling Of Shrssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 47%

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Augmentation of autophagy by atorvastatin via Akt/mTOR pathway in spontaneously hypertensive rats

Wang

Qian

et al. 2015

Hypertens Res

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“…13) In vivo studies revealed that atorvastatin inhibited LV remodeling in spontaneously hypertensive rats (SHRs) through the induction of cardiomyocyte apoptosis; up-regulation of myocardial P27 protein expression; down-regulation of PKD/MEF2D activation; and decreasing blood pressure, serum uric acid concentration, and myocardial angiotensin II concentration. 6,[14][15][16] The effects of atorvastatin on myocardial CTGF expression in SHRs are not clear. SHRs develop high blood pressure and LV hypertrophy at an early age, and are a commonly used model of essential hypertension in humans.…”

Section: H Ypertension That Results In Left Ventricular (Lv) Hyper-mentioning

confidence: 99%

“…The apoptosis rate in myocardiocytes in the SHR-DW group was reduced, whereas 12-week treatment with atorvastatin induced myocardiocyte apoptosis accompanied by alleviated LV remodeling. This indicated that in SHRs aged [8][9][10][11][12][13][14][15][16][17][18][19][20] weeks, reduced apoptosis in myocardiocytes was involved in the development of LV remodeling, and that the effects of atorvastatin on apoptosis may be applicable only to SHRs of this age. Studies on myocardiocyte apoptosis and the effects of atorvastatin on this parameter in SHRs older than 20 weeks should be carried out.…”

mentioning

confidence: 99%

Atorvastatin Prevents Left Ventricular Remodeling in Spontaneously Hypertensive Rats

Zhao

Zhang

et al. 2010

Int. Heart J.

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SummaryStatins improve left ventricular (LV) remodeling in spontaneously hypertensive rats (SHRs). This study was designed to investigate the effects of atorvastatin administered in the early stage on LV remodeling in SHRs, and to explore the underlying mechanisms.Sixteen male 8-week-old SHRs were randomized to receive distilled water (SHR-DW) or atorvastatin (SHR-ATV) for 12 weeks. Age-matched male Wistar-Kyoto (WKY) rats gavaged with distilled water served as controls. LV remodeling was evaluated, myocardial CTGF expression levels were detected using Western blotting, and cardiomyocyte apoptosis was detected with the TUNEL method.Compared with WKY and SHR-DW, atorvastatin treatment significantly decreased systolic blood pressure in SHRs; atorvastatin significantly inhibited LV remodeling, as indicated by the reduced LV weight/body weight ratio (SHR-ATV: 4.0 ± 0.4 versus SHR-DW: 4.7 ± 0.4 mg/g, P < 0.05), cardiomyocyte diameter (SHR-ATV: 16.2 ± 2.8 versus SHR-DW: 19.0 ± 1.0 μm, P < 0.05), and interstitial fibrosis (SHR-ATV: 3.3 ± 2.1 versus SHR-DW: 4.5 ± 1.8%, P < 0.05). Compared with WKY, myocardial CTGF expression was significantly increased and cardiomyocyte apoptosis decreased in SHRs. Compared with the SHR-DW group, atorvastatin treatment significantly inhibited myocardial CTGF expression (SHR-ATV: 0.69 ± 0.21 versus SHR-DW: 1.12 ± 0.27, P < 0.05) and induced cardiomyocyte apoptosis in SHRs (SHR-ATV: 5.2 ± 0.6 versus SHR-DW: 1.9 ± 0.3%, P < 0.05).The results indicate that early-stage administration of atorvastatin effectively prevented LV remodeling in SHRs, and that inhibition of myocardial CTGF expression and induction of cardiomyocyte apoptosis may be the underlying mechanisms. ( ) contributed to the development and evolution of LV remodeling in hypertensive models. Investigations into the role of cardiomyocyte apoptosis in the development of LV hypertrophy in animal models produced discrepant results. Some research groups found that cardiomyocyte apoptosis increased in LV hypertrophy and inhibition of apoptosis could alleviate ventricular hypertrophy, 4,5) whereas other research teams found contrary results.6) Further studies to elucidate the relationship between cardiomyocyte apoptosis and hypertensive LV hypertrophy are therefore required.Connective tissue growth factor (CTGF), a newly defined cell factor which takes part in regulation of the secretion of extracellular matrix by fibroblasts, has important roles in the fibrosis of various organs, including the liver, kidney, and heart ventricles. 7,8) Recent studies have indicated that inhibition of expression of CTGF protein may be a therapeutic target of myocardial fibrosis. 9,10) Several studies confirmed the beneficial effects of statins on inhibiting hypertension-induced LV remodeling. Simvastatin mitigates hypertension-induced myocardial fibrosis through down-regulation of myocardial CTGF. 11)In rats with pulmonary arterial hypertension, simvastatin prevents and, to some extent, reverses vascular remodeling via down-regulation of CTGF gene expre...

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The Biology and Therapeutic Implications of HDACs in the Heart

McKinsey

2011

Handbook of Experimental Pharmacology

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The heart responds to stresses such as chronic hypertension and myocardial infarction by undergoing a remodeling process that is associated with myocyte hypertrophy, myocyte death, inflammation and fibrosis, often resulting in impaired cardiac function and heart failure. Recent studies have revealed key roles for histone deacetylases (HDACs) as both positive and negative regulators of pathological cardiac remodeling, and small molecule HDAC inhibitors have demonstrated efficacy in animal models of heart failure. This chapter reviews the functions of individual HDAC isoforms in the heart and highlights issues that need to be addressed to enable development of novel HDAC-directed therapies for cardiovascular indications.

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Atorvastatin reverses cardiac remodeling possibly through regulation of Protein Kinase D/Myocyte Enhancer Factor 2D activation in spontaneously hypertensive rats

Cited by 21 publications

References 35 publications

Augmentation of autophagy by atorvastatin via Akt/mTOR pathway in spontaneously hypertensive rats

Augmentation of autophagy by atorvastatin via Akt/mTOR pathway in spontaneously hypertensive rats

Atorvastatin Prevents Left Ventricular Remodeling in Spontaneously Hypertensive Rats

The Biology and Therapeutic Implications of HDACs in the Heart

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