Treatment of Familial Hypercholesterolemia: Is There a Need Beyond Statin Therapy?

Raper, Anna; Kolansky, Daniel M.; Cuchel, Marina

doi:10.1007/s11883-011-0215-y

Cited by 20 publications

(7 citation statements)

References 51 publications

(57 reference statements)

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“…Statins are clinically approved for the treatment of hypercholesterolemia (Faiz et al, 2012; Raper et al, 2012). However, increasing clinical and experimental evidence demonstrates a variety of beneficial effects beyond the reduction of serum cholesterol (Lopez-Pedrera et al, 2012).…”

Section: The Selectivity Of Rho/rock Inhibition In Human Diseasesmentioning

confidence: 99%

Rho-kinase: regulation, (dys)function, and inhibition

Amin

Dubey²,

Zhang

et al. 2013

Biological Chemistry

157

133

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In a variety of normal and pathological cell types, Rho-kinases I and II (ROCKI/II) play a pivotal role in the organization of the nonmuscle and smooth muscle cytoskeleton and adhesion plaques as well as in the regulation of transcription factors. Thus, ROCKI/II activity regulates cellular contraction, motility, morphology, polarity, cell division, and gene expression. Emerging evidence suggests that dysregulation of the Rho-ROCK pathways at different stages is linked to cardiovascular, metabolic, and neurodegenerative diseases as well as cancer. This review focuses on the current status of understanding the multiple functions of Rho-ROCK signaling pathways and various modes of regulation of Rho-ROCK activity, thereby orchestrating a concerted functional response.

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Section: The Selectivity Of Rho/rock Inhibition In Human Diseasesmentioning

confidence: 99%

Rho-kinase: regulation, (dys)function, and inhibition

Amin

Dubey²,

Zhang

et al. 2013

Biological Chemistry

157

133

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“…Statin drugs are capable of inhibiting the synthesis of endogenous cholesterol by competitive inhibition of HMGCR (4). Statins were originally used to treat hypercholesterolemia (5), but have since been found to exert many pleiotropic effects (6), including immunomodulatory, anti-inflammatory (7), and neuroprotective (8) effects. Clinical studies have demonstrated that statins can be used to treat diseases that are not clearly related to low-density lipoprotein cholesterol (LDL-C) or cholesterol (9,10).…”

Section: Introductionmentioning

confidence: 99%

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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“…Statins were originally discovered as Penicillium citrinum -derived metabolites with extremely potent inhibitory properties against HMGCR (Endo, Hasumi, & Negishi, 1985; Endo, Kuroda, & Tsujita, 1976). From this discovery, lovastatin was developed and used to reduce endogenous cholesterol synthesis serving as a valuable pharmacologic treatment for patients with hypercholesterolemia (Alberts, 1988b) (Montecucco, Quercioli, Mirabelli-Badenier, Viviani, & Mach, 2012; Raper, Kolansky, & Cuchel, 2012; Shepherd, et al, 1995a; Q. Zhou & Liao, 2009).…”

Section: Introductionmentioning

confidence: 99%

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

Yeganeh

Wiechec

Ande

et al. 2014

Pharmacology & Therapeutics

139

129

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The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs (‘statins’) directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD), and cancer.

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Treatment of Familial Hypercholesterolemia: Is There a Need Beyond Statin Therapy?

Cited by 20 publications

References 51 publications

Rho-kinase: regulation, (dys)function, and inhibition

Rho-kinase: regulation, (dys)function, and inhibition

Inhibition of the mevalonate pathway improves myocardial fibrosis

Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease

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