Top

Clinical Reviews in Allergy & Immunology

Published in:

Open Access 01-04-2018

MicroRNAs: New Therapeutic Targets for Familial Hypercholesterolemia?

Authors: Amir Abbas Momtazi, Maciej Banach, Matteo Pirro, Evan A. Stein, Amirhossein Sahebkar

Published in: Clinical Reviews in Allergy & Immunology | Issue 2/2018

Abstract

Familial hypercholesterolemia (FH) is the most common inherited form of dyslipidemia and a major cause of premature cardiovascular disease. Management of FH mainly relies on the efficiency of treatments that reduce plasma low-density lipoprotein (LDL) cholesterol (LDL-C) concentrations. MicroRNAs (miRs) have been suggested as emerging regulators of plasma LDL-C concentrations. Notably, there is evidence showing that miRs can regulate the post-transcriptional expression of genes involved in the pathogenesis of FH, including LDLR, APOB, PCSK9, and LDLRAP1. In addition, many miRs are located in genomic loci associated with abnormal levels of circulating lipids and lipoproteins in human plasma. The strong regulatory effects of miRs on the expression of FH-associated genes support of the notion that manipulation of miRs might serve as a potential novel therapeutic approach. The present review describes miRs-targeting FH-associated genes that could be used as potential therapeutic targets in patients with FH or other severe dyslipidemias.

Najam O, Ray KK (2015) Familial hypercholesterolemia: a review of the natural history, diagnosis, and management. Cardiology and therapy 4(1):25–38CrossRefPubMedPubMedCentral

Collaboration, E.A.S.F.H.S et al (2016) Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: rationale and design of the global EAS familial Hypercholesterolaemia studies collaboration. Atheroscler Suppl 22:1–32CrossRef

Vallejo-Vaz AJ et al (2015) Familial hypercholesterolaemia: a global call to arms. Atherosclerosis 243(1):257–259CrossRefPubMed

Anderson TJ et al (2013) 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 29(2):151–167CrossRefPubMed

Henderson R et al (2016) The genetics and screening of familial hypercholesterolaemia. J Biomed Sci 23(1):39CrossRefPubMedPubMedCentral

Cuchel M et al (2014) Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 35(32):2146–2157CrossRefPubMedPubMedCentral

Nordestgaard BG et al (2013) Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. Eur Heart J 34(45):3478–3490CrossRefPubMedPubMedCentral

Cannon CP et al (2015) Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 372(25):2387–2397CrossRefPubMed

Catapano AL et al (2016) 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J 37(39):2999–3058CrossRefPubMed

10.

Banach M et al (2017) PoLA/CFPiP/PCS Guidelines for the Management of Dyslipidaemias for Family Physicians 2016. Arch Med Sci 13(1):1–45CrossRefPubMed

11.

de Goma EM et al (2016) Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: data from the CASCADE-FH Registry. Circ Cardiovasc Genet 9(3):240–249CrossRef

12.

Marais AD et al (2008) A dose-titration and comparative study of rosuvastatin and atorvastatin in patients with homozygous familial hypercholesterolaemia. Atherosclerosis 197(1):400–406CrossRefPubMed

13.

Raal FJ et al (1997) Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia. Atherosclerosis 135(2):249–256CrossRefPubMed

14.

Gagné C et al (2002) Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 105(21):2469–2475CrossRefPubMed

15.

Momtazi AA et al (2017) Regulation of PCSK9 by nutraceuticals. Pharmacol Res 120:157–169CrossRefPubMed

16.

Consortium EP (2004) The ENCODE (ENCyclopedia of DNA elements) project. Science 306(5696):636–640CrossRef

17.

Burnett JC, Rossi JJ (2012) RNA-based therapeutics: current progress and future prospects. Chem Biol 19(1):60–71CrossRefPubMedPubMedCentral

18.

Lam JK et al (2015) siRNA versus miRNA as therapeutics for gene silencing. Molecular Therapy-Nucleic Acids 4:e252CrossRefPubMedPubMedCentral

19.

Deng Y et al (2014) Therapeutic potentials of gene silencing by RNA interference: principles, challenges, and new strategies. Gene 538(2):217–227CrossRefPubMed

20.

Davidson BL, McCray PB (2011) Current prospects for RNA interference-based therapies. Nat Rev Genet 12(5):329–340CrossRefPubMedPubMedCentral

21.

Kim DH, Rossi JJ (2007) Strategies for silencing human disease using RNA interference. Nat Rev Genet 8(3):173–184CrossRefPubMed

22.

Agrawal N et al (2003) RNA interference: biology, mechanism, and applications. Microbiol Mol Biol Rev 67(4):657–685CrossRefPubMedPubMedCentral

23.

Pecot CV et al (2011) RNA interference in the clinic: challenges and future directions. Nat Rev Cancer 11(1):59–67CrossRefPubMed

24.

Pillai RS, Bhattacharyya SN, Filipowicz W (2007) Repression of protein synthesis by miRNAs: how many mechanisms? Trends Cell Biol 17(3):118–126CrossRefPubMed

25.

Petersen CP et al (2006) Short RNAs repress translation after initiation in mammalian cells. Mol Cell 21(4):533–542CrossRefPubMed

26.

Schultheis B et al (2014) First-in-human phase I study of the liposomal RNA interference therapeutic Atu027 in patients with advanced solid tumors. J Clin Oncol 32(36):4141–4148CrossRefPubMed

27.

Tabernero J et al (2013) First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov 3(4):406–417CrossRefPubMed

28.

Bader AG et al (2011) Developing therapeutic microRNAs for cancer. Gene Ther 18(12):1121–1126CrossRefPubMedPubMedCentral

29.

Momtazi AA et al. (2016) Curcumin as a MicroRNA regulator in cancer: a review

30.

DeVincenzo J et al (2010) A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus. Proc Natl Acad Sci 107(19):8800–8805CrossRefPubMedPubMedCentral

31.

Chandra PK et al (2012) Inhibition of hepatitis C virus replication by intracellular delivery of multiple siRNAs by nanosomes. Mol Ther 20(9):1724–1736CrossRefPubMedPubMedCentral

32.

Sendi H et al (2015) miR-122 decreases HCV entry into hepatocytes through binding to the 3′ UTR of OCLN mRNA. Liver Int 35(4):1315–1323CrossRefPubMed

33.

Erdmann VA, Poller W, and Barciszewski J (2008) RNA technologies in cardiovascular medicine and research. Springer

34.

Fitzgerald K et al (2017) A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 376(1):41–51CrossRefPubMed

35.

Behlke MA (2006) Progress towards in vivo use of siRNAs. Mol Ther 13(4):644–670CrossRefPubMed

36.

Ray KK, et al. (2017) Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med

37.

van Rooij E, Purcell AL, Levin AA (2012) Developing microRNA therapeutics. Circ Res 110(3):496–507CrossRefPubMed

38.

Bader AG, Brown D, Winkler M (2010) The promise of microRNA replacement therapy. Cancer Res 70(18):7027–7030CrossRefPubMedPubMedCentral

39.

Vidal L et al (2005) Making sense of antisense. Eur J Cancer 41(18):2812–2818CrossRefPubMed

40.

Jackson AL et al (2006) Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complementarity. RNA 12(7):1179–1187CrossRefPubMedPubMedCentral

41.

Birmingham A et al (2006) 3′ UTR seed matches, but not overall identity, are associated with RNAi off-targets. Nat Methods 3(3):199–204CrossRefPubMed

42.

Fedorov Y et al (2006) Off-target effects by siRNA can induce toxic phenotype. RNA 12(7):1188–1196CrossRefPubMedPubMedCentral

43.

Grimm D et al (2006) Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441(7092):537–541CrossRefPubMed

44.

Liu Z, Sall A, Yang D (2008) MicroRNA: an emerging therapeutic target and intervention tool. Int J Mol Sci 9(6):978–999CrossRefPubMedPubMedCentral

45.

Goedeke L et al (2016) miRNA regulation of LDL-cholesterol metabolism. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1861(12):2047–2052

46.

Condorelli G, Latronico MV, Dorn GW (2010) microRNAs in heart disease: putative novel therapeutic targets? Eur Heart J 31(6):649–658CrossRefPubMedPubMedCentral

47.

Martino F et al (2015) Circulating miR-33a and miR-33b are up-regulated in familial hypercholesterolaemia in paediatric age. Clin Sci 129(11):963–972CrossRef

48.

Creemers EE, Tijsen AJ, Pinto YM (2012) Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease? Circ Res 110(3):483–495CrossRefPubMed

49.

Sahebkar A et al (2016) Editorial: microRNA-33 inhibition: a potential adjunct to statin therapy? Curr Vasc Pharmacol 14(4):321–322CrossRefPubMed

50.

Bouchie A (2013) First microRNA mimic enters clinic, Nature Research

51.

Qiu Z, Dai Y (2014) Roadmap of miR-122-related clinical application from bench to bedside. Expert Opin Investig Drugs 23(3):347–355CrossRefPubMed

52.

Van Rooij E and Kauppinen S (2014) Development of microRNA therapeutics is coming of age. EMBO molecular medicine, p. e201100899

53.

Soria LF et al (1989) Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci 86(2):587–591CrossRefPubMedPubMedCentral

54.

Soutar AK, Naoumova RP (2007) Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nature clinical practice Cardiovascular medicine 4(4):214–225CrossRefPubMed

55.

Agarwal V et al (2015) Predicting effective microRNA target sites in mammalian mRNAs. elife 4:e05005CrossRefPubMedCentral

56.

Alvarez ML et al (2015) MicroRNA-27a decreases the level and efficiency of the LDL receptor and contributes to the dysregulation of cholesterol homeostasis. Atherosclerosis 242(2):595–604CrossRefPubMedPubMedCentral

57.

Goedeke L et al (2015) miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice. Atherosclerosis 243(2):499–509CrossRefPubMedPubMedCentral

58.

Wagschal A et al (2015) Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. Nat Med 21(11):1290–1297CrossRefPubMedPubMedCentral

59.

Goedeke L et al (2015) MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat Med 21(11):1280–1289CrossRefPubMedPubMedCentral

60.

Jiang H et al (2015) microRNA-185 modulates low density lipoprotein receptor expression as a key posttranscriptional regulator. Atherosclerosis 243(2):523–532CrossRefPubMed

61.

Bai J et al. (2016) A retrospective study of NENs and miR-224 promotes apoptosis of BON-1 cells by targeting PCSK9 inhibition. Oncotarget

62.

He M et al (2017) Pro-inflammation NF-kappaB signaling triggers a positive feedback via enhancing cholesterol accumulation in liver cancer cells. J Exp Clin Cancer Res 36(1):15CrossRefPubMedPubMedCentral

63.

Li Y et al (2016) MicroRNA-132 cause apoptosis of glioma cells through blockade of the SREBP-1c metabolic pathway related to SIRT1. Biomed Pharmacother 78:177–184CrossRefPubMed

64.

Zhang H et al (2014) MicroRNA-449 suppresses proliferation of hepatoma cell lines through blockade lipid metabolic pathway related to SIRT1. Int J Oncol 45(5):2143–2152CrossRefPubMed

65.

Li X et al (2013) MicroRNA-185 and 342 inhibit tumorigenicity and induce apoptosis through blockade of the SREBP metabolic pathway in prostate cancer cells. PLoS One 8(8):e70987CrossRefPubMedPubMedCentral

66.

Yang M et al (2014) Identification of miR-185 as a regulator of de novo cholesterol biosynthesis and low density lipoprotein uptake. J Lipid Res 55(2):226–238CrossRefPubMedPubMedCentral

67.

Xu Y et al. (2015) A metabolic stress-inducible miR-34a-HNF4 [alpha] pathway regulates lipid and lipoprotein metabolism. Nature communications, 6

68.

Soh J, Hussain MM (2013) Supplementary site interactions are critical for the regulation of microsomal triglyceride transfer protein by microRNA-30c. Nutrition & metabolism 10(1):56CrossRef

69.

Soh J et al (2013) MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion. Nat Med 19(7):892–900CrossRefPubMedPubMedCentral

70.

Hsu S-H et al (2012) Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Invest 122(8):2871–2883CrossRefPubMedPubMedCentral

71.

Esau C et al (2006) miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 3(2):87–98CrossRefPubMed

72.

Zhang L et al (2012) Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA. Cell Res 22(1):107–126CrossRefPubMed

73.

Seidah NG (2016) New developments in proprotein convertase subtilisin-kexin 9’s biology and clinical implications. Curr Opin Lipidol 27(3):274–281CrossRefPubMed

74.

Paciullo F, et al. (2017) PCSK9 at the crossroad of cholesterol metabolism and immune function during infections. J Cell Physiol

75.

Momtazi AA, Banach M, Sahebkar A (2017) PCSK9 inhibitors in sepsis: a new potential indication? Expert Opin Investig Drugs 26(2):137–139CrossRefPubMed

76.

Momtazi AA, et al. (2017) PCSK9 and diabetes: is there a link? Drug Discovery Today

77.

Momtazi AA, Banach M, and Sahebkar A (2017) PCSK9 inhibitors in sepsis: a new potential indication?, Taylor & Francis

78.

Abifadel M et al (2003) Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 34(2):154–156CrossRefPubMed

79.

Cohen J et al (2005) Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 37(2):161–165CrossRefPubMed

80.

Cohen JC et al (2006) Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 354(12):1264–1272CrossRefPubMed

81.

Zhao Z et al (2006) Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 79(3):514–523CrossRefPubMedPubMedCentral

82.

Hooper AJ et al (2007) The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 193(2):445–448CrossRefPubMed

83.

Robinson JG et al (2015) Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 372(16):1489–1499CrossRefPubMed

84.

Sabatine MS et al (2015) Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 372(16):1500–1509CrossRefPubMed

85.

Sabatine MS, et al. (2017) Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med

86.

Hooper AJ, Burnett JR (2013) Anti-PCSK9 therapies for the treatment of hypercholesterolemia. Expert Opin Biol Ther 13(3):429–435CrossRefPubMed

87.

Navarese EP et al (2015) Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia. A systematic review and meta-analysis effects of PCSK9 antibodies in adults with hypercholesterolemia. Ann Intern Med 163(1):40–51CrossRefPubMed

88.

Zhang X-L et al (2015) Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med 13(1):123CrossRefPubMedPubMedCentral

89.

Kazi DS et al (2016) Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA 316(7):743–753CrossRefPubMed

90.

Place RF et al (2008) MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci 105(5):1608–1613CrossRefPubMedPubMedCentral

91.

Zambrano T et al (2015) Impact of 3’UTR genetic variants in PCSK9 and LDLR genes on plasma lipid traits and response to atorvastatin in Brazilian subjects: a pilot study. Int J Clin Exp Med 8(4):5978PubMedPubMedCentral

92.

Cornier M-A, Eckel RH (2014) Non-traditional dosing of statins in statin-intolerant patients—is it worth a try? Current Atherosclerosis Reports 17(2):475CrossRef

93.

Finkel JB, Duffy D (2015) 2013 ACC/AHA cholesterol treatment guideline: paradigm shifts in managing atherosclerotic cardiovascular disease risk. Trends in Cardiovascular Medicine 25(4):340–347CrossRefPubMed

94.

Raal FJ, Blom DJ Anacetrapib in familial hypercholesterolaemia: pros and cons. Lancet 385(9983):2124–2126

95.

Raal FJ et al (2016) Pediatric experience with mipomersen as adjunctive therapy for homozygous familial hypercholesterolemia. Journal of clinical lipidology 10(4):860–869CrossRefPubMed

96.

McGowan MP, Moriarty PM, Backes JM (2014) The effects of mipomersen, a second-generation antisense oligonucleotide, on atherogenic (apoB-containing) lipoproteins in the treatment of homozygous familial hypercholesterolemia. Clinical Lipidology 9(5):487–503CrossRef

97.

Rader DJ, Kastelein JJP (2014) Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation 129(9):1022–1032CrossRefPubMed

98.

Gouni-Berthold I, Berthold HK (2015) Mipomersen and lomitapide: two new drugs for the treatment of homozygous familial hypercholesterolemia. Atheroscler Suppl 18:28–34CrossRefPubMed

99.

Cuchel M, Blom DJ, Averna MR (2014) Clinical experience of lomitapide therapy in patients with homozygous familial hypercholesterolaemia. Atheroscler Suppl 15(2):33–45CrossRefPubMed

100.

Dai K, Hussain MM (2012) NR2F1 disrupts synergistic activation of the MTTP gene transcription by HNF-4α and HNF-1α. J Lipid Res 53(5):901–908CrossRefPubMedPubMedCentral

101.

Sheena V et al (2005) Transcriptional regulation of human microsomal triglyceride transfer protein by hepatocyte nuclear factor-4α. J Lipid Res 46(2):328–341CrossRefPubMed

102.

Hirokane H et al (2004) Bile acid reduces the secretion of very low density lipoprotein by repressing microsomal triglyceride transfer protein gene expression mediated by hepatocyte nuclear factor-4. J Biol Chem 279(44):45685–45692CrossRefPubMed

103.

Choi SE et al (2013) Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT. Aging Cell 12(6):1062–1072CrossRefPubMed

104.

Hussain MM et al (2012) Multiple functions of microsomal triglyceride transfer protein. Nutrition & metabolism 9(1):14CrossRef

105.

Hussain MM, Shi J, Dreizen P (2003) Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res 44(1):22–32CrossRefPubMed

106.

Zhou L et al (2016) MicroRNAs regulating apolipoprotein B-containing lipoprotein production. Biochimica et Biophysica Acta (BBA)-molecular and cell biology of lipids 1861(12):2062–2068

107.

Soutar AK, Naoumova RP, Traub LM (2003) Genetics, clinical phenotype, and molecular cell biology of autosomal recessive hypercholesterolemia. Arterioscler Thromb Vasc Biol 23(11):1963–1970CrossRefPubMed

Title: MicroRNAs: New Therapeutic Targets for Familial Hypercholesterolemia?
Authors: Amir Abbas Momtazi
Maciej Banach
Matteo Pirro
Evan A. Stein
Amirhossein Sahebkar
Publication date: 01-04-2018
Publisher: Springer US
Published in: Clinical Reviews in Allergy & Immunology / Issue 2/2018
Print ISSN: 1080-0549
Electronic ISSN: 1559-0267
DOI: https://doi.org/10.1007/s12016-017-8611-x

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2018

Review: Diagnosing Common Variable Immunodeficiency Disorder in the Era of Genome Sequencing

The Comparative Safety of TNF Inhibitors in Ankylosing Spondylitis—a Meta-Analysis Update of 14 Randomized Controlled Trials

Anti-interleukin 5 Therapy for Eosinophilic Asthma: a Meta-analysis of Randomized Clinical Trials

Effectiveness, Tolerability, and Safety of Belimumab in Patients with Refractory SLE: a Review of Observational Clinical-Practice-Based Studies

Chitin and Its Effects on Inflammatory and Immune Responses

Myeloid Cells and Chronic Liver Disease: a Comprehensive Review

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials