Atorvastatin ameliorates cardiac fibrosis and improves left ventricular diastolic function in hypertensive diastolic heart failure model rats

Akahori, Hirokuni; Tsujino, Takeshi; Naito, Yoshiro; Matsumoto, Mika; Sasaki, Nozomu; Iwasaku, Toshihiro; Eguchi, Akiyo; Sawada, Hisashi; Hirotani, Shinichi; Masuyama, Tohru

doi:10.1097/hjh.0000000000000184

Cited by 35 publications

(17 citation statements)

References 36 publications

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“…In addition, HSP47 has been found to be associated with fibrosis level after myocardial infarction (43). Another study suggested that the beneficial effect of atorvastatin on cardiac fibrosis may be due to lowered HSP47 levels (34). The results of the present study are consistent with the aforementioned studies, with statins having the strongest effect among the tested drugs.…”

Section: Discussionsupporting

confidence: 90%

“…The mechanism of these effects may be related to suppression of the MVA pathway and downstream GTPase activity (30,31). Some cell culture and animal studies have suggested that statins can prevent the development of cardiac hypertrophy and fibrosis (32)(33)(34)(35), which may reduce ventricular compliance and is a major cause of cardiac diastolic dysfunction (36). A meta-analysis of 11 eligible studies, including 17,985 patients with heart failure with a preserved ejection fraction demonstrated that statin therapy may be associated with improved survival rates in these patients (37).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of the mevalonate pathway improves myocardial fibrosis

Shen

Liang

et al. 2021

Exp Ther Med

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The mevalonate (MVA) pathway serves an important role in ventricular remodeling. Targeting the MVA pathway has protective effects against myocardial fibrosis. The present study aimed to investigate the mechanism behind these effects. Primary cultured cardiac fibroblasts from C57BL/6 mice were treated in vitro in 5 groups: i) negative control; ii) angiotensin II (Ang II) model (1x10-5 mol/l); iii) Ang II + rosuvastatin (ROS); iv) Ang II + alendronate (ALE); and v) Ang II + fasudil (FAS). Collagen and crystal violet staining were used to assess morphological changes in cardiac fibroblasts. Reverse transcription quantitative PCR and western blotting were used to analyze the expression of key signaling molecules involved in the MVA pathway. Collagen staining in the ALE, FAS, and ROS groups was weak compared with the Ang II group, while the rate of cell proliferation in the ROS, ALE, and FAS groups was slower compared with that in the Ang II group. In addition, the expression of key signaling molecules in the MVA pathway, including transforming growth factor-β1 (TGF-β1), heat shock protein 47 (HSP47), collagen type I α1 (COL1A1), vascular endothelial growth factor 2 (VEGF2) and fibroblast growth factor 2 (FGF2), was decreased in the FAS and ROS groups compared with the Ang II model. Compared with the Ang II group, 3-Hydroxy-3-Methylglutaryl-CoA reductase (HMGCR) gene expression was significantly lowered in the drug intervention groups, whereas farnesyl pyrophosphate synthase (FDPS) expression was downregulated in the ALE group, but elevated in the FAS and ROS groups. Compared with that in the Ang II group, ras homolog family member A (RhoA) expression was downregulated in the FAS and ROS groups, whilst mevalonate kinase expression was reduced in the ROS group. Protein expression of TGF-β1, COL1A1 and HSP47 were decreased following intervention with each of the three drugs compared with the Ang II group. Overall, rosuvastatin, aledronate and fasudil decreased the proliferation of myocardial fibroblasts and inhibited collagen synthesis. Rosuvastatin had the strongest protective effects against myocardial fibrosis compared with the other drugs tested, suggesting this to be a potential agent for the clinical treatment of cardiovascular disease.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Inhibition of the mevalonate pathway improves myocardial fibrosis

Shen

Liang

et al. 2021

Exp Ther Med

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“…Aldosterone may have an adverse effect on cardiac and vascular fibrosis 24 34. Although statins have been shown to decrease myocardial fibrosis in several animal models,9 10 clinical evidence is rare. One study showed that statins decrease circulating fibrosis markers in patients with HF 12.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, atorvastatin appeared to directly inhibit collagen production by cardiac fibroblasts in a human cardiac fibroblast cell culture 7. In animal studies, statins have been found to improve postmyocardial infarction myocardial ﬁbrosis,8 and to ameliorate cardiac fibrosis and improve diastolic function in a rat model with diastolic HF 9. In double-knockout mice with metabolic syndrome, rosuvastatin was also shown to decrease myocardial fibrosis 10.…”

Section: Introductionmentioning

confidence: 97%

Effects of 12 Weeks of Atorvastatin Therapy on Myocardial Fibrosis and Circulating Fibrosis Biomarkers in Statin-NaïVe Patients with Hypertension with Atherosclerosis

Chang

Lee

et al. 2016

Journal of Investigative Medicine

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“…Accordingly, it has been hypothesized that the action of statins to reduce the accumulation and inflammation of epicardial adipose tissue might not only have a salutary effect on nearby coronary vessels, but also on the underlying ventricular myocardium. Such an action could explain why, in experimental models, statins ameliorate microcirculatory derangements, cardiac fibrosis and their associated echocardiographic ventricular filling abnormalities . As a result of these effects, the anti‐inflammatory action of statins might be useful (particularly in people with metabolic disorder) by acting primarily to prevent the development of HFpEF, rather than heart failure with a reduced ejection fraction (HFrEF) .…”

Section: Differential Effects Of Statins In Preserved Vs Reduced Ejementioning

confidence: 99%

Are the effects of drugs to prevent and to treat heart failure always concordant? The statin paradox and its implications for understanding the actions of antidiabetic medications

Packer

2018

European J of Heart Fail

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Most treatments for chronic heart failure are effective both in preventing its onset and reducing its progression. However, statins prevent the development of heart failure, but they do not decrease morbidity and mortality in those with established heart failure. This apparent discordance cannot be explained by an effect to prevent interval myocardial infarctions. Instead, it seems that the disease that statins were preventing in trials of patients with a metabolic disorder was different from the disease that they were treating in trials of chronic heart failure. The most common phenotype of heart failure in patients with obesity and diabetes is heart failure with a preserved ejection fraction (HFpEF). In this disorder, the anti-inflammatory effects of statins might ameliorate myocardial fibrosis and cardiac filling abnormalities, but these actions may have little relevance to patients with heart failure and a reduced ejection fraction (HFrEF), whose primary derangement is cardiomyocyte loss and stretch. These distinctions may explain why statins were ineffective in trials that focused on HFrEF, but have been reported to produce favourable effects in observational studies of HFpEF. Similarly, selective cytokine antagonists were ineffective in HFrEF, but have been associated with benefits in HFpEF. These observations may have important implications for our understanding of the effects of antihyperglycaemic medications. Glucagon-like peptide-1 receptor agonists have had neutral effects on heart failure events in people at risk for HFpEF, but have exerted deleterious actions in HFrEF. Similarly, sodium-glucose co-transporter 2 inhibitors, which exert anti-inflammatory effects and reduce heart failure events in patients who are prone to HFpEF, may not be effective in HFrEF. The distinctions between HFrEF and HFpEF may explain why the effects of drugs on heart failure events in diabetes trials may not be relevant to their use in patients with systolic dysfunction.

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Atorvastatin ameliorates cardiac fibrosis and improves left ventricular diastolic function in hypertensive diastolic heart failure model rats

Abstract: Atorvastatin administration ameliorates cardiac fibrosis and improves left ventricular diastolic function in Dahl salt-sensitive rats. Lowering HSP47 by atorvastatin via inhibition of Rho-Rho kinase pathway is suggested as a mechanism.

Cited by 35 publications

References 36 publications

Inhibition of the mevalonate pathway improves myocardial fibrosis

Inhibition of the mevalonate pathway improves myocardial fibrosis

Effects of 12 Weeks of Atorvastatin Therapy on Myocardial Fibrosis and Circulating Fibrosis Biomarkers in Statin-NaïVe Patients with Hypertension with Atherosclerosis

Are the effects of drugs to prevent and to treat heart failure always concordant? The statin paradox and its implications for understanding the actions of antidiabetic medications

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