Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications

Gorabi, Armita Mahdavi; Kiaie, Nasim; Hajighasemi, Saeideh; Banach, Maciej; Penson, Peter E.; Jamialahmadi, Tannaz; Sahebkar, Amirhossein

doi:10.3390/jcm8122051

Cited by 77 publications

(49 citation statements)

References 107 publications

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“…Beyond lowering cholesterol, statins have been associated with a range of beneficial pleiotropic effects including anti-inflammatory, antioxidant and immunomodulatory effects, inhibition of platelet activation, regulation of pyroptosis, and increased plaque stability [12][13][14]. For example, statins mediate a dose-dependent decrease in C-reactive protein [15], may impact renal function [16,17], and attenuate postpartum cardiovascular dysfunction in a rat preeclampsia model [18].…”

Section: Introductionmentioning

confidence: 99%

Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components

Turner

Pirmohamed

2019

JCM

137

126

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Statins are a cornerstone in the pharmacological prevention of cardiovascular disease. Although generally well tolerated, a small subset of patients experience statin-related myotoxicity (SRM). SRM is heterogeneous in presentation; phenotypes include the relatively more common myalgias, infrequent myopathies, and rare rhabdomyolysis. Very rarely, statins induce an anti-HMGCR positive immune-mediated necrotizing myopathy. Diagnosing SRM in clinical practice can be challenging, particularly for mild SRM that is frequently due to alternative aetiologies and the nocebo effect. Nevertheless, SRM can directly harm patients and lead to statin discontinuation/non-adherence, which increases the risk of cardiovascular events. Several factors increase systemic statin exposure and predispose to SRM, including advanced age, concomitant medications, and the nonsynonymous variant, rs4149056, in SLCO1B1, which encodes the hepatic sinusoidal transporter, OATP1B1. Increased exposure of skeletal muscle to statins increases the risk of mitochondrial dysfunction, calcium signalling disruption, reduced prenylation, atrogin-1 mediated atrophy and pro-apoptotic signalling. Rare variants in several metabolic myopathy genes including CACNA1S, CPT2, LPIN1, PYGM and RYR1 increase myopathy/rhabdomyolysis risk following statin exposure. The immune system is implicated in both conventional statin intolerance/myotoxicity via LILRB5 rs12975366, and a strong association exists between HLA-DRB1*11:01 and anti-HMGCR positive myopathy. Epigenetic factors (miR-499-5p, miR-145) have also been implicated in statin myotoxicity. SRM remains a challenge to the safe and effective use of statins, although consensus strategies to manage SRM have been proposed. Further research is required, including stringent phenotyping of mild SRM through N-of-1 trials coupled to systems pharmacology omics- approaches to identify novel risk factors and provide mechanistic insight.

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Section: Introductionmentioning

confidence: 99%

Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components

Turner

Pirmohamed

2019

JCM

137

126

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“…Of note, intraperitoneally injected evodiamine increased eNOS, Akt, and CaMKII phosphorylation in WT, but not TRPV1 −/− mice. NO has long been known to promote neovascularization by stimulating both angiogenesis and vasculogenesis [136,[164][165][166]. Consistently, the Matrigel plug assay confirmed that evodiamine promoted angiogenesis in vivo, although neovascularization was prevented in TRPV1 −/− and eNOS-deficient (eNOS −/− ) mice [163].…”

Section: Chemical Stimulation Of Trpv1 Promotes Angiogenesis In a Camentioning

confidence: 62%

Endothelial TRPV1 as an Emerging Molecular Target to Promote Therapeutic Angiogenesis

Negri

Faris

Rosti

et al. 2020

Cells

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Therapeutic angiogenesis represents an emerging strategy to treat ischemic diseases by stimulating blood vessel growth to rescue local blood perfusion. Therefore, injured microvasculature may be repaired by stimulating resident endothelial cells or circulating endothelial colony forming cells (ECFCs) or by autologous cell-based therapy. Endothelial Ca2+ signals represent a crucial player in angiogenesis and vasculogenesis; indeed, several angiogenic stimuli induce neovessel formation through an increase in intracellular Ca2+ concentration. Several members of the Transient Receptor Potential (TRP) channel superfamily are expressed and mediate Ca2+-dependent functions in vascular endothelial cells and in ECFCs, the only known truly endothelial precursor. TRP Vanilloid 1 (TRPV1), a polymodal cation channel, is emerging as an important player in endothelial cell migration, proliferation, and tubulogenesis, through the integration of several chemical stimuli. Herein, we first summarize TRPV1 structure and gating mechanisms. Next, we illustrate the physiological roles of TRPV1 in vascular endothelium, focusing our attention on how endothelial TRPV1 promotes angiogenesis. In particular, we describe a recent strategy to stimulate TRPV1-mediated pro-angiogenic activity in ECFCs, in the presence of a photosensitive conjugated polymer. Taken together, these observations suggest that TRPV1 represents a useful target in the treatment of ischemic diseases.

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“…Multiple animal experimental and clinical studies have demonstrated favourable effects associated with nitrate supplementation-based boosting of the enterosalivary nitrate-nitrite-NO pathway, including reduced blood pressure, a cytoprotective effect against myocardial ischaemia-reperfusion injury, reversal of vascular dysfunction in older adults, cardiac protection through restoration of NO homeostasis, improved angiogenesis following chronic ischaemia, and an advantageous influence on cerebral vasospasm in subarachnoid haemorrhage [52][53][54][55][56][57][58][59]. Notably, the favourable cholesterol-independent effects of statins, such as reduced blood pressure, improved angiogenesis, and benefits in patients with heart failure, are realized through increased expression and function of endothelial NO synthases by a variety of mechanisms and pathways [60]. Hou et al demonstrated that homocysteine-induced endothelial dysfunction, a well-known risk factor in cardiovascular disease, is reversed by enhancing endothelial NO synthase [61].…”

Section: Role Of No In Biological Processesmentioning

confidence: 99%

Antiseptic mouthwash, the nitrate–nitrite–nitric oxide pathway, and hospital mortality: a hypothesis generating review

Blot

2020

Intensive Care Med

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Meta-analyses and several large cohort studies have demonstrated that antiseptic mouthwashes are associated with mortality in hospitalized patients. A clear pathogenic mechanism is lacking, leading to controversy and a reluctance to abandon or limit the use of antiseptic mouthwashes. Here, we generate the hypothesis that a disturbance in nitric oxide homeostasis by antiseptic mouthwashes may be responsible for the observed increase in mortality risk. Nitric oxide is essential in multiple physiological processes, and a reduction in nitric oxide bioavailability is associated with the occurrence or worsening of pathologies, such as atherosclerosis, diabetes, and sepsis. Oral facultative anaerobic bacteria are essential for the enterosalivary nitrate-nitrite-nitric oxide pathway due to their capacity to reduce nitrate to nitrite. Nitrate originates from dietary sources or from the active uptake by salivary glands of circulating nitrate, which is then excreted in the saliva. Because antiseptic mouthwashes eradicate the oral bacterial flora, this nitric oxide-generating pathway is abolished, which may result in nitric oxide-deficient conditions potentially leading to life-threatening complications such as ischaemic heart events or sepsis.

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Statin-Induced Nitric Oxide Signaling: Mechanisms and Therapeutic Implications

Cited by 77 publications

References 107 publications

Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components

Statin-Related Myotoxicity: A Comprehensive Review of Pharmacokinetic, Pharmacogenomic and Muscle Components

Endothelial TRPV1 as an Emerging Molecular Target to Promote Therapeutic Angiogenesis

Antiseptic mouthwash, the nitrate–nitrite–nitric oxide pathway, and hospital mortality: a hypothesis generating review

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