Pleiotropic Effects of Statin in Therapy in Heart Failure: A Review

Correale, Michele; Abruzzese, Silvia; Greco, C; Concilio, Morena; Brunetti, Natale Daniele

doi:10.2174/1570161112999141127161508

Cited by 14 publications

(12 citation statements)

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“…A number of outlying clinical observations suggest that simvastatin and other statins can work in another way than the lowering of cholesterol and induces so-called "pleiotropic effects" that are independent of their effects on lipids and lipoproteins [10,22]. It has been explored that some of the cholesterol-independent effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, reducing oxidative stress and inflammation, decreasing activation of the blood coagulation cascade, and inhibition of platelet aggregation [2,6,25,38].…”

Section: Introductionmentioning

confidence: 99%

Statin treatment decreases serum angiostatin levels in patients with ischemic heart disease

et al. 2015

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Section: Introductionmentioning

confidence: 99%

Statin treatment decreases serum angiostatin levels in patients with ischemic heart disease

et al. 2015

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“…A growing body of evidence suggests that the inhibition of cholesterol synthesis itself may not be the primary cause of these deleterious side effects. Instead, the inhibition of protein prenylation (Wang et al 2008;Correale et al 2014) and an impaired mitochondrial homeostasis (Golomb and Evans 2008;Apostolopoulou et al 2015) may be among the underlying mechanisms leading to the side effects of statins. One proposed mechanism suggests that reduced levels of the ubiquinone Coenzyme Q 10 (CoQ 10 ) cause impaired mitochondrial calcium homeostasis in the muscles of statin-treated humans (Galtier et al 2012;Sirvent et al 2012), but this is highly controversial (Apostolopoulou et al 2015;Auer et al 2016).…”

mentioning

confidence: 99%

The UPRmt Protects Caenorhabditis elegans from Mitochondrial Dysfunction by Upregulating Specific Enzymes of the Mevalonate Pathway

Oks

Lewin

Goncalves³

et al. 2018

Genetics

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The mevalonate pathway is the primary target of the cholesterol-lowering drugs statins, some of the most widely prescribed medicines of all time. The pathway's enzymes not only catalyze the synthesis of cholesterol but also of diverse metabolites such as mitochondrial electron carriers and isoprenyls. Recently, it has been shown that one type of mitochondrial stress response, the UPR, can protect yeast, , and cultured human cells from the deleterious effects of mevalonate pathway inhibition by statins. The mechanistic basis for this protection, however, remains unknown. Using, we found that the UPR does not directly affect the levels of the statin target HMG-CoA reductase, the rate-controlling enzyme of the mevalonate pathway in mammals. Instead, in the UPR upregulates the first dedicated enzyme of the pathway, HMG-CoA synthase (HMGS-1). A targeted RNA interference (RNAi) screen identified two UPR transcription factors, ATFS-1 and DVE-1, as regulators of HMGS-1 A comprehensive analysis of the pathway's enzymes found that, in addition to HMGS-1, the UPR upregulates enzymes involved with the biosynthesis of electron carriers and geranylgeranylation intermediates. Geranylgeranylation, in turn, is requisite for the full execution of the UPR 3response. Thus, the UPR acts in at least three coordinated, compensatory arms to upregulate specific branches of the mevalonate pathway, thereby alleviating mitochondrial stress. We propose that statin-mediated inhibition of the mevalonate pathway blocks this compensatory system of the UPR and consequentially impedes mitochondrial homeostasis. This effect is likely one of the principal bases for the adverse side effects of statins.

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“…Our results showed that the myocardium from patients with established dyslipidemia is less susceptible to injury. However, the majority of the patients in our study (95%) were taking HMG-CoA reductase inhibitors (statins), which in addition to reducing serum cholesterol exert pleiotropic effects that could have influenced the susceptibility of the myocardium to I/R injury [23]. Experimental studies have implicated an increase in oxidative stress and a diminished bioavailability in NO in the altered response to I/R injury in hypercholesterolemia [24].…”

Section: Discussionmentioning

confidence: 99%

Response of the human myocardium to ischemic injury and preconditioning: The role of cardiac and comorbid conditions, medical treatment, and basal redox status

et al. 2017

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BackgroundThe diseased human myocardium is highly susceptible to ischemia/reoxygenation (I/R)-induced injury but its response to protective interventions such as ischemic preconditioning (IPreC) is unclear. Cardiac and other pre-existing clinical conditions as well as previous or ongoing medical treatment may influence the myocardial response to I/R injury and protection. This study investigated the effect of both on myocardial susceptibility to I/R-induced injury and the protective effects of IPreC.Methods and resultsAtrial myocardium from cardiac surgery patients (n = 300) was assigned to one of three groups: aerobic control, I/R alone, and IPreC. Lactate dehydrogenase leakage, as a marker of cell injury, and cell viability were measured. The basal redox status was determined in samples from 90 patients.The response to I/R varied widely. Myocardium from patients with aortic valve disease was the most susceptible to injury whereas myocardium from dyslipidemia patients was the least susceptible. Tissue from females was better protected than tissue from males. Myocardium from patients with mitral valve disease was the least responsive to IPreC. The basal redox status was altered in the myocardium from patients with mitral and aortic valve disease.ConclusionsThe response of the myocardium to I/R and IPreC is highly variable and influenced by the underlying cardiac pathology, dyslipidemia, sex, and the basal redox status. These results should be taken into account in the design of future clinical studies on the prevention of I/R injury and protection.

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Pleiotropic Effects of Statin in Therapy in Heart Failure: A Review

Cited by 14 publications

References 0 publications

Statin treatment decreases serum angiostatin levels in patients with ischemic heart disease

Statin treatment decreases serum angiostatin levels in patients with ischemic heart disease

The UPRmt Protects Caenorhabditis elegans from Mitochondrial Dysfunction by Upregulating Specific Enzymes of the Mevalonate Pathway

Response of the human myocardium to ischemic injury and preconditioning: The role of cardiac and comorbid conditions, medical treatment, and basal redox status

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