Anti-fibrotic effects of statin drugs: A review of evidence and mechanisms

Dolivo, David M.; Reed, Charlotte R.; Gargiulo, Kristine A.; Rodrigues, Adrian E.; Galiano, Robert D.; Mustoe, Thomas A.; Hong, Seok Jong

doi:10.1016/j.bcp.2023.115644

Cited by 10 publications

(7 citation statements)

References 145 publications

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“…To provide additional support to the notion that the abrogation of TGF-β1 induced COL1A1 gene expression stimulation by Simvastatin is mediated by inhibition of RhoA activation, we showed that TGF-β1 effects on the cytoskeleton were also affected by Simvastatin and by RhoA siRNA. These results are in agreement with other studies demonstrating that Simvastatin inhibits the expression of some profibrotic markers including CTGF, α-smooth muscle actin (αSMA), and fibronectin through the inhibition of RhoA activation [44][45][46][47].…”

Section: Discussionsupporting

confidence: 93%

Simvastatin Abrogates TGF-β Induced Stimulation of Normal Human Dermal Fibroblast Collagen Gene Expression in Culture

Piera-Velazquez,

Huaman-Vargas,

Louneva

et al. 2024

J Cancer Biol Res

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A potent stimulation of fibroblast collagen production is one of the crucial pleotropic effects of transforming growth factor β (TGF-β) and has been considered to play a crucial role in the pathogenesis of fibrotic diseases including Systemic Sclerosis and Pulmonary Fibrosis. This complex process involves numerous intracellular reactions mediated by canonical Smad-dependent or non-canonical pathways that transduce the extracellular stimuli into the nucleus. Here, we demonstrated that Simvastatin, a widely used statin, induces a potent inhibition of TGF-β1 profibrotic effects in cultured normal human dermal fibroblasts, and studied the molecular mechanisms involved in these effects. We also examined Simvastatin modulation of TGF-β1 induced fibroblast to myofibroblast transition. Normal human dermal fibroblasts were cultured with various concentrations of Simvastatin in the presence or absence of TGF-β1 (10ng/ml) for 24, 48, and 72 h. The effects of Simvastatin on TGF-β1 stimulation of COL1A1 expression and type 1 collagen production were examined. Assessment of Smad2/3 and Erk1/2 phosphorylation, chromatin immunoprecipitation assays for Sp1 transcription factor binding to the COL1A1 proximal promoter, siRNA-mediated RhoA knockdown, and F-actin immunofluorescence microscopy was performed to examine the molecular mechanisms involved.

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Section: Discussionsupporting

confidence: 93%

Simvastatin Abrogates TGF-β Induced Stimulation of Normal Human Dermal Fibroblast Collagen Gene Expression in Culture

Piera-Velazquez,

Huaman-Vargas,

Louneva

et al. 2024

J Cancer Biol Res

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“…One of the drugs that was demonstrated to solubilize at high strength in this vehicle was simvastatin, a lipophilic statin with low oral availability. This is a drug with pleiotropic effects and many potential applications beyond the control of dyslipidemia, like anti-cancer [ 23 ], anti-fibrotic [ 24 ], neuroprotective [ 25 , 26 ], and bone regeneration [ 27 ] applications, among others. Some of these applications could benefit from an alternative liquid formulation for, for example, intranasal administration, which has the potential to enhance brain delivery [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Innovative Aqueous Nanoemulsion Prepared by Phase Inversion Emulsification with Exceptional Homogeneity

Pires,

Fernandes,

Nina

et al. 2023

Pharmaceutics

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Formulating low-solubility or low-permeability drugs is a challenge, particularly with the low administration volumes required in intranasal drug delivery. Nanoemulsions (NE) can solve both issues, but their production and physical stability can be challenging, particularly when a high proportion of lipids is necessary. Hence, the aim of the present work was to develop a NE with good solubilization capacity for lipophilic drugs like simvastatin and able to promote the absorption of drugs with low permeability like fosphenytoin. Compositions with high proportion of two lipids were screened and characterized. Surprisingly, one of the compositions did not require high energy methods for high droplet size homogeneity. To better understand formulation factors important for this feature, several related compositions were evaluated, and their relative cytotoxicity was screened. Optimized compositions contained a high proportion of propylene glycol monocaprylate NF, formed very homogenous NE using a low-energy phase inversion method, solubilized simvastatin at high drug strength, and promoted a faster intranasal absorption of the hydrophilic prodrug fosphenytoin. Hence, a new highly homogeneous NE obtained by a simple low-energy method was successfully developed, which is a potential alternative for industrial application for the solubilization and protection of lipophilic actives, as well as (co-)administration of hydrophilic molecules.

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“…Multiple studies have provided evidence supporting the use of statins for lipidlowering purposes in reducing mortality rates in patients with coronary artery disease, both in primary and secondary prevention settings [15][16][17][18][19][20]. The favorable effects of statins are linked to their pleiotropic effects with anti-inflammatory activity, improvement in endothelial function, reduction in oxidative stress, and antithrombotic activity [21,22]. In an animal model with myocardial ischemia, statins have been shown to reduce myocardial injury and stimulate nitric oxide production, showing some direct vascular and cardioprotective effects of statins [23].…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of High-Intensity versus Low-to-Moderate Intensity Statin Therapy in Patients Undergoing Rotational Atherectomy for Calcified Coronary Artery Disease

Choi,

Jung,

Her

et al. 2023

Life

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(1) Background: Moderate-intensity statin therapy, when compared to high-intensity statin therapy in Asian populations, has shown no significant difference in cardiovascular prognosis in small studies. The aim of this study was to compare the prognosis of patients based on statin intensity following rotational atherectomy (RA) during high-complexity percutaneous coronary intervention (PCI). (2) Methods: The ROCK registry, a multicenter retrospective study, included patients who had undergone rotational atherectomy (RA) during percutaneous coronary intervention (PCI) at nine tertiary medical centers in South Korea between January 2010 and October 2019. The patients were divided into high-intensity statin (H-statin) and moderate/low-intensity statin (M/L-statin) therapy groups. The primary endpoint includes outcomes (cardiac death, target vessel myocardial infarction (MI), and target vessel revascularization (TVR)) within an 18-month follow-up period. (3) Results: In this registry, a total of 540 patients with 583 lesions were included. We excluded 39 lesions from the analysis due to the absence of statin usage. The H-statin group had 394 lesions and the M/L-statin group had 150 lesions. There were no significant differences in baseline characteristics, procedural adverse events without heart failure history, triglycerides, or medications between the two groups. The procedural success rate showed a significant difference between the two groups. Multivariate analysis did not show a significant association between M/L-statin therapy and an increased risk of the primary endpoint. In propensity score matching analysis, no significant difference was observed in the primary endpoint either. (4) Conclusions: In high-complex RA PCI, moderate/low-intensity statin therapy is not inferior to high-intensity statin therapy in Korea.

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Anti-fibrotic effects of statin drugs: A review of evidence and mechanisms

Cited by 10 publications

References 145 publications

Simvastatin Abrogates TGF-β Induced Stimulation of Normal Human Dermal Fibroblast Collagen Gene Expression in Culture

Simvastatin Abrogates TGF-β Induced Stimulation of Normal Human Dermal Fibroblast Collagen Gene Expression in Culture

Innovative Aqueous Nanoemulsion Prepared by Phase Inversion Emulsification with Exceptional Homogeneity

Comparative Analysis of High-Intensity versus Low-to-Moderate Intensity Statin Therapy in Patients Undergoing Rotational Atherectomy for Calcified Coronary Artery Disease

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