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Int J Mol Sci. 2024;25(5):ijms25052593.

The Role of Cilostazol, a Phosphodiesterase-3 Inhibitor, in the Development of Atherosclerosis and Vascular Biology: A Review with Meta-Analysis.

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제1저자 손민지 · 교신저자 임수

PMID 38473840 PMC10932209 DOI 10.3390/ijms25052593 IF 5.6 내분비대사내과
소속 (1)
  1. Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Republic of Korea.

Abstract

Atherosclerotic cardiovascular disease (ASCVD) stands as the leading global cause of mortality. Addressing this vital and pervasive condition requires a multifaceted approach, in which antiplatelet intervention plays a pivotal role, together with antihypertensive, antidiabetic, and lipid-lowering therapies. Among the antiplatelet agents available currently, cilostazol, a phosphodiesterase-3 inhibitor, offers a spectrum of pharmacological effects. These encompass vasodilation, the impediment of platelet activation and aggregation, thrombosis inhibition, limb blood flow augmentation, lipid profile enhancement through triglyceride reduction and high-density lipoprotein cholesterol elevation, and the suppression of vascular smooth muscle cell proliferation. However, the role of cilostazol has not been clearly documented in many guidelines for ASCVD. We comprehensively reviewed the cardiovascular effects of cilostazol within randomized clinical trials that compared it to control or active agents and involved individuals with previous coronary artery disease or stroke, as well as those with no previous history of such conditions. Our approach demonstrated that the administration of cilostazol effectively reduced adverse cardiovascular events, although there was less evidence regarding its impact on myocardial infarction. Most studies have consistently reported its favorable effects in reducing intermittent claudication and enhancing ambulatory capacity in patients with peripheral arterial disease. Furthermore, cilostazol has shown promise in mitigating restenosis following coronary stent implantation in patients with acute coronary syndrome. While research from more diverse regions is still needed, our findings shed light on the broader implications of cilostazol in the context of atherosclerosis and vascular biology, particularly for individuals at high risk of ASCVD.

Keywords

aspirinatherosclerosiscardiovascular diseasescilostazolplatelet aggregation inhibitors

Figures

Figure 3
Figure 3 Forest plots of cilostazol in composite major adverse cardiovascular events (MACEs) compared with the following: (A) the control, (B) aspirin, and (C) clopidogrel. CI, confidence interval; RR, risk ratio.
Figure 4
Figure 4 Forest plots of cilostazol in cardiovascular and safety events: (A) myocardial infarction, (B) stroke, (C) cardiovascular death, (D) all-cause death, (E) bleeding, and (F) discontinuation of the study drug.
Figure 1
Figure 1 Mechanisms of action of cilostazol. Cilostazol inhibits phosphodiesterase-3 in various cell types including platelets, vascular cells, myocytes, and adipocytes, which affects several pathways resulting in vasodilation and enhanced blood perfusion. Cilostazol induces nitric oxide (NO) release from endothelial cells and activates calcium-dependent potassium channels in vascular smooth muscle cells, leading to vasodilation. This action leads to the upregulation of the protein kinase A (PKA), and eventually causing arterial dilatation and platelet inactivation. Furthermore, cilostazol attenuates the activation of platelets, thus facilitating blood perfusion. Abbreviations: 5′AMP, 5′-adenosine monophosphate; cAMP, cyclic adenosine monophosphate; eNOS, endothelial nitric oxide synthase; JAK2, Janus kinase 2; PDE-3, phosphodiesterase-3; PKA, protein kinase A; PPARγ, peroxisome proliferator-activated receptor gamma; STAT3, signal transducer and activator of transcription 3; TG, triglycerides; and TXA2, thromboxane A2.
Figure 2
Figure 2 PRISMA flow diagram for studies included in the current meta-analysis.
Figure 5
Figure 5 Forest plots of cilostazol’s effect on composite major adverse cardiovascular events (MACEs) and individual components categorized by regional background: (A) MACE, (B) myocardial infarction (MI), (C) stroke, and (D) cardiovascular death. CI, confidence interval; RR, risk ratio.
Figure 6
Figure 6 Anti-atherosclerotic effect of cilostazol.

그림 출처: PubMed Central 공개 논문 (PMC10932209)

Conflict of interest statement

The authors declare no conflicts of interest.

그 밖의 정보
출판 형태
Meta-Analysis, Journal Article, Review
저널
International journal of molecular sciences · eISSN 1422-0067
전자 출판
2024-02-23
MeSH
Humans · Cilostazol · Phosphodiesterase 3 Inhibitors · Atherosclerosis* · Peripheral Arterial Disease* · Platelet Aggregation Inhibitors · Cholesterol, HDL · Phosphoric Diester Hydrolases · Biology · Tetrazoles · Drug Therapy, Combination
Substances
Cilostazol · Phosphodiesterase 3 Inhibitors · Platelet Aggregation Inhibitors · Cholesterol, HDL · Phosphoric Diester Hydrolases · Tetrazoles
참고문헌
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