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Pleiotropic effects of statins: new therapeutic targets in drug design

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Abstract

The HMG Co-enzyme inhibitors and new lipid-modifying agents expand their new therapeutic target options in the field of medical profession. Statins have been described as the most effective class of drugs to reduce serum cholesterol levels. Since the discovery of the first statin nearly 30 years ago, these drugs have become the main therapeutic approach to lower cholesterol levels. The present scientific research demonstrates numerous non-lipid modifiable effects of statins termed as pleiotropic effects of statins, which could be beneficial for the treatment of various devastating disorders. The most important positive effects of statins are anti-inflammatory, anti-proliferative, antioxidant, immunomodulatory, neuroprotective, anti-diabetes, and antithrombotic, improving endothelial dysfunction and attenuating vascular remodeling besides many others which are discussed under the scope of this review. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil-containing protein kinase (ROCK), and their agonistic action on peroxisome proliferator-activated receptors (PPARs) can be viewed as the principle mechanisms underlying the pleiotropic effects of statins. With gradually increasing knowledge of new therapeutic targets of statins, their use has also been advocated in chronic inflammatory disorders for example rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE). In the scope of review, we highlight statins and their pleiotropic effects with reference to their harmful and beneficial effects as a novel approach for their use in the treatment of devastating disorders.

Pleiotropic effect of statins

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Abbreviations

ACE:

Angiotensin-converting enzyme

AMI:

Acute myocardial infarction

AP-1:

Activator protein-1

ApoC-III:

Apolipoprotein type III

AT1:

Angiotensin II type 1 receptor

β-ARK:

Beta-adrenergic kinase

CRP:

C-reactive protein

eNOS:

Endothelial nitric oxide synthase

ET-1:

Endothelin type 1

FA:

Fatty acids

FPP:

Farnesyl pyrophosphate

GGPP:

Geranylgeranyl pyrophosphate

HDL:

High-density lipoproteins

HMG-CoA:

3-Hydroxy-3-methylglutaryl coenzyme A

ICAM-1:

Intercellular adhesion molecule type 1

IFN-gamma:

Interferon gamma

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

LDL:

Low-density lipoproteins

MCP-1:

Monocyte chemoattractant protein type 1

MHC-II:

Major histocompatibility complex class II

MMP:

Matrix metalloproteinase

NAD(P)H:

Nicotinamide adenine dinucleotide phosphate

NF-κB:

Nuclear factor kappa B

PAI-1:

Plasminogen activator inhibitor type 1

PPAR:

Peroxisome proliferator activated receptor

RAS:

Renin-angiotensin system

ROS:

Reactive oxygen species

TG:

Triglycerides

TGF-:

Transforming growth factor beta

Th:

T helper

TNF-α:

Tumor necrosis factor alpha

tPA:

Tissue plasminogen activator

TXA2 :

Thromboxane A2

VCAM-1:

Vascular cell adhesion molecule type 1

VEGF:

Vascular endothelial growth factor

VLDL:

Very-low-density lipoproteins

VSMC:

Vascular smooth muscle cell

ADR :

Adverse drug reaction.

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Authors and Affiliations

  1. Department of Pharmacology, I.S.F College of Pharmacy, Moga, Punjab, 142001, India

    Puneet Kumar

  2. Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India

    Onkar Bedi & Veena Dhawan

  3. Department of Pharmacology, Post Graduate Institute of Medical Education & Research (PGIMER), Chandigarh, India

    P. L. Sharma

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  1. Onkar Bedi
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  2. Veena Dhawan
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  3. P. L. Sharma
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  4. Puneet Kumar
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Correspondence to Puneet Kumar.

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Additional information

Chemical compounds studied in this article:

Atorvastatin (PubChem CID: 60823)

Simvastatin (PubChem CID: 54454)

Fluvastatin (PubChem CID: 1548972)

Lovastatin (PubChem CID: 53232)

Pravastatin (PubChem CID: 54687)

Rosuvastatin (PubChem CID: 446157)

Pitavastatin (PubChem CID: 5282452)

Highlights

•Statins are effective in primary and secondary prevention of cardiovascular disease and other disorders like brain disorders, inflammatory disorders, etc.

•Statins play a vital role in nephrogenic diabetes insipidus with reference to aquaporin-2 water channels.

•Other highlight of this review about statins is there risk factors or ADRs related to their prolong use.

•Relation of statins with other multiple pathways like Rac, PPARs, Rho/ROCK, etc. other than to their HMG Co-enzyme inhibitor activity.

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Bedi, O., Dhawan, V., Sharma, P.L. et al. Pleiotropic effects of statins: new therapeutic targets in drug design. Naunyn-Schmiedeberg's Arch Pharmacol 389, 695–712 (2016). https://doi.org/10.1007/s00210-016-1252-4

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  • DOI: https://doi.org/10.1007/s00210-016-1252-4

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