Cyclin‑dependent kinase 9 may as a novel target in downregulating the atherosclerosis inflammation (Review)

Han,Yeming; Ζhan,Yang; Ηou,Guihua; Li,Li

doi:10.3892/br.2014.322

Cyclin‑dependent kinase 9 may as a novel target in downregulating the atherosclerosis inflammation (Review)

Authors:
- Yeming Han
- Yang Ζhan
- Guihua Ηou
- Li Li
View Affiliations

Affiliations: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China, Institute of Experimental Nuclear Medicine, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
Published online on: July 31, 2014 https://doi.org/10.3892/br.2014.322
Pages: 775-779

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Inflammation is a key component of atherosclerosis. Genes coding for inflammatory or anti‑inflammatory molecules are considered good candidates for estimating the risk of developing atherosclerosis. Cyclin‑dependent kinase 9 (CDK9), the kinase of positive transcription elongation factor b (P‑TEFb), is crucial in the cell cycle and apoptosis. Previous studies have focused on its inhibition of immune cells for the resolution of inflammation. Considering the effects of inflammation in the pathogenicity of atherosclerosis, decreasing inflammation through the inhibition of CDK9 may be useful for the prognosis of atherosclerosis. The aim of this review was to examine whether inhibition of the CDK9 monocyte may affect the process of inflammation by acting on the cytokine secretion and interacting with endothelial cells (ECs). Thus, CDK9 may be a novel target for the diagnosis and therapy of atherosclerosis.

View Figures

View References

1	García-Gómez C, Bianchi M, de la Fuente D, Badimon L, Padró T, Corbella E and Pintó X: Inflammation, lipid metabolism and cardiovascular risk in rheumatoid arthritis: A qualitative relationship? World J Orthop. 5:304–311. 2014.PubMed/NCBI
2	Randolph GJ: Mechanisms that regulate macrophage burden in atherosclerosis. Circ Res. 114:1757–1771. 2014. View Article : Google Scholar : PubMed/NCBI
3	Ait-Oufella H, Sage AP, Mallat Z and Tedgui A: Adaptive (T and B cells) immunity and control by dendritic cells in atherosclerosis. Circ Res. 114:1640–1660. 2014. View Article : Google Scholar : PubMed/NCBI
4	Mangoni AA: Folic acid, inflammation, and atherosclerosis: false hopes or the need for better trials? Clin Chim Acta. 367:11–19. 2006. View Article : Google Scholar : PubMed/NCBI
5	Incalcaterra E, Accardi G, Balistreri CR, Caimi G, Candore G, Caruso M and Caruso C: Pro-inflammatory genetic markers of atherosclerosis. Curr Atheroscler Rep. 15:329–335. 2013. View Article : Google Scholar
6	Raman K, Chong M, Akhtar-Danesh GG, D’Mello M, Hasso R, Ross S, Xu F and Paré G: Genetic markers of inflammation and their role in cardiovascular disease. Can J Cardiol. 29:67–74. 2013. View Article : Google Scholar : PubMed/NCBI
7	Van-Assche T, Huygelen V, Crabtree MJ and Antoniades C: Gene therapy targeting inflammation in atherosclerosis. Curr Pharm Des. 17:4210–4223. 2011. View Article : Google Scholar : PubMed/NCBI
8	Lu XT, Zhao YX, Zhang Y and Jiang F: Psychological stress, vascular inflammation, and atherogenesis: potential roles of circulating cytokines. J Cardiovasc Pharmacol. 62:6–12. 2013. View Article : Google Scholar : PubMed/NCBI
9	Martinet W, Schrijvers DM and De Meyer GR: Molecular and cellular mechanisms of macrophage survival in atherosclerosis. Basic Res Cardiol. 107:297–309. 2012. View Article : Google Scholar : PubMed/NCBI
10	Di Gregoli K and Johnson JL: Role of colony-stimulating factors in atherosclerosis. Curr Opin Lipidol. 23:412–421. 2012.PubMed/NCBI
11	Chen LJ, Lim SH, Yeh YT, Lien SC and Chiu JJ: Roles of microRNAs in atherosclerosis and restenosis. J Biomed Sci. 19:79–92. 2012. View Article : Google Scholar : PubMed/NCBI
12	Schmerwitz UK, Sass G, Khandoga AG, et al: Flavopiridol protects against inflammation by attenuating leukocyte-endothelial interaction via inhibition of cyclin-dependent kinase 9. Arterioscler Thromb Vasc Biol. 31:280–288. 2011. View Article : Google Scholar
13	Peng J, Zhu Y, Milton JT and Price DH: Identification of multiple cyclin subunits of human P-TEFb. Genes Dev. 12:755–762. 1998. View Article : Google Scholar : PubMed/NCBI
14	Licastro F, Candore G, Lio D, Porcellini E, Colonna-Romano G, Franceschi C and Caruso C: Innate immunity and inflammation in ageing: a key for understanding age-related diseases. Immun Ageing. 2:82005. View Article : Google Scholar : PubMed/NCBI
15	Stephens JW and Humphries SE: The molecular genetics of cardiovascular disease: clinical implications. J Intern Med. 253:120–127. 2003. View Article : Google Scholar : PubMed/NCBI
16	Lipszyc PS, Cremaschi GA, Zorrilla-Zubilete M, Bertolino ML, Capani F, Genaro AM and Wald MR: Niacin modulates pro-inflammatory cytokine secretion. A potential mechanism involved in its anti-atherosclerotic effect. Open Cardiovasc Med J. 7:90–98. 2013. View Article : Google Scholar : PubMed/NCBI
17	Baumli S, Hole AJ, Wang LZ, Noble ME and Endicott JA: The CDK9 tail determines the reaction pathway of positive transcription elongation factor b. Cell. 20:1788–1795. 2012.PubMed/NCBI
18	Budhiraja S, Famiglietti M, Bosque A, Planelles V and Rice AP: Cyclin T1 and CDK9 T-loop phosphorylation are downregulated during establishment of HIV-1 latency in primary resting memory CD4⁺ T cells. J Virol. 87:1211–1220. 2013. View Article : Google Scholar : PubMed/NCBI
19	Wang S and Fischer PM: Cyclin-dependent kinase 9: a key transcriptional regulator and potential drug target in oncology, virology and cardiology. Trends Pharmacol Sci. 29:302–313. 2008. View Article : Google Scholar : PubMed/NCBI
20	Sunagawa Y, Morimoto T, Takaya T, et al: Cyclin-dependent kinase-9 is a component of the p300/GATA4 complex required for phenylephrine-induced hypertrophy in cardiomyocytes. J Biol Chem. 285:9556–9568. 2010. View Article : Google Scholar : PubMed/NCBI
21	Garriga J and Grana X: Cellular control of gene expression by T-type cyclin/CDK9 complexes. Gene. 337:15–23. 2004. View Article : Google Scholar : PubMed/NCBI
22	Wang Y, Liu XY and De Clercq E: Role of the HIV-1 positive elongation factor P-TEFb and inhibitors thereof. Mini Rev Med Chem. 9:379–385. 2009. View Article : Google Scholar : PubMed/NCBI
23	Marshall RM and Grana X: Mechanisms controlling CDK9 activity. Front Biosci. 11:2598–2613. 2006. View Article : Google Scholar : PubMed/NCBI
24	Foskett SM, Ghose R, Tang DN, Lewis DE and Rice AP: Antiapoptotic function of Cdk9 (TAK/P-TEFb) in U937 promonocytic cells. J Virol. 75:1220–1228. 2001. View Article : Google Scholar : PubMed/NCBI
25	Fu TJ, Peng J, Lee G, Price DH and Flores O: Cyclin K functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription. J Biol Chem. 274:34527–34530. 1999. View Article : Google Scholar : PubMed/NCBI
26	Marshall RM, Salerno D, Garriga J and Grana X: Cyclin T1 expression is regulated by multiple signaling pathways and mechanisms during activation of human peripheral blood lymphocytes. J Immunol. 175:6402–6411. 2005. View Article : Google Scholar : PubMed/NCBI
27	Kanazawa S, Okamoto T and Peterlin BM: Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection. Immunity. 12:61–70. 2000. View Article : Google Scholar : PubMed/NCBI
28	Heidenreich S: Monocyte CD14: a multifunctional receptor engaged in apoptosis from both sides. J Leukoc Biol. 65:737–743. 1999.PubMed/NCBI
29	Herrmann CH, Carroll RG, Wei P, Jones KA and Rice AP: Tat-associated kinase, TAK, activity is regulated by distinct mechanisms in peripheral blood lymphocytes and promonocytic cell lines. J Virol. 72:9881–9888. 1998.PubMed/NCBI
30	Miranda MB, Dyer KF, Grandis JR and Johnson DE: Differential activation of apoptosis regulatory pathways during monocytic vs granulocytic differentiation: a requirement for Bcl-X(L)and XIAP in the prolonged survival of monocytic cells. Leukemia. 17:390–400. 2003. View Article : Google Scholar
31	Xaus J, Cardo M, Valledor AF, Soler C, Lloberas J and Celada A: Interferon gamma induces the expression of p21waf-1 and arrests macrophage cell cycle, preventing induction of apoptosis. Immunity. 11:103–113. 1999. View Article : Google Scholar : PubMed/NCBI
32	Yang X, Gold MO, Tang DN, Lewis DE, Aguilar-Cordova E, Rice AP and Herrmann CH: TAK, an HIV Tat-associated kinase, is a member of the cyclin-dependent family of protein kinases and is induced by activation of peripheral blood lymphocytes and differentiation of promonocytic cell lines. Proc Natl Acad Sci USA. 94:12331–12336. 1997. View Article : Google Scholar : PubMed/NCBI
33	Leitch AE, Lucas CD, Marwick JA, Duffin R, Haslett C and Rossi AG: Cyclin-dependent kinases 7 and 9 specifically regulate neutrophil transcription and their inhibition drives apoptosis to promote resolution of inflammation. Cell Death Differ. 19:1950–1961. 2012. View Article : Google Scholar
34	Berberich N, Uhl B, Joore J, Schmerwitz UK, Mayer BA, Reichel CA, Krombach F, Zahler S, Vollmar AM and Furst R: Roscovitine blocks leukocyte extravasation by inhibition of cyclin-dependent kinases 5 and 9. Br J Pharmacol. 163:1086–1098. 2011. View Article : Google Scholar : PubMed/NCBI
35	Johnson N and Shapiro GI: Cyclin-dependent kinases (cdks) and the DNA damage response: rationale for cdk inhibitor-chemotherapy combinations as an anticancer strategy for solid tumors. Expert Opin Ther Targets. 14:1199–1212. 2010. View Article : Google Scholar
36	Wang LM and Ren DM: Flavopiridol, the first cyclin-dependent kinase inhibitor: recent advances in combination chemotherapy. Mini Rev Med Chem. 10:1058–1070. 2010. View Article : Google Scholar : PubMed/NCBI
37	Krystof V, Baumli S and Furst R: Perspective of cyclin-dependent kinase 9 (CDK9) as a drug target. Curr Pharm Des. 18:2883–2890. 2012. View Article : Google Scholar : PubMed/NCBI
38	Sekine C, Sugihara T, Miyake S, Hirai H, Yoshida M, Miyasaka N and Kohsaka H: Successful treatment of animal models of rheumatoid arthritis with small-molecule cyclin-dependent kinase inhibitors. J Immunol. 180:1954–1961. 2008. View Article : Google Scholar : PubMed/NCBI
39	Li L, Wang H, Kim Js, Pihan G and Boussiotis V: The cyclin dependent kinase inhibitor (R)-roscovitine prevents alloreactive T cell clonal expansion and protects against acute GvHD. Cell Cycle. 8:1794–1802. 2009. View Article : Google Scholar : PubMed/NCBI
40	Zoja C, Casiraghi F, Conti S, Corna D, Rottoli D, Cavinato RA, Remuzzi G and Benigni A: Cyclin-dependent kinase inhibition limits glomerulonephritis and extends lifespan of mice with systemic lupus. Arthritis Rheum. 56:1629–1637. 2007. View Article : Google Scholar : PubMed/NCBI
41	Jia HY, Chen F, Chen JZ, Wu SS, Wang J, Cao QY, Chen Z and Zhu HH: MicroRNA expression profiles related to early stage murine concanavalin A-induced hepatitis. Cell Physiol Biochem. 33:1933–1944. 2014. View Article : Google Scholar : PubMed/NCBI
42	Hou T, Ray S and Brasier AR: The functional role of an interleukin 6-inducible CDK9.STAT3 complex in human gamma-fibrinogen gene expression. J Biol Chem. 282:37091–37102. 2007. View Article : Google Scholar : PubMed/NCBI
43	Leitch AE, Haslett C and Rossi AG: Cyclin-dependent kinase inhibitor drugs as potential novel anti-inflammatory and pro-resolution agents. Br J Pharmacol. 158:1004–1016. 2009. View Article : Google Scholar : PubMed/NCBI
44	Galli SJ, Borregaard N and Wynn TA: Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol. 12:1035–1044. 2011. View Article : Google Scholar : PubMed/NCBI
45	Puga I, Cols M, Barra CM, et al: B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol. 13:170–180. 2011. View Article : Google Scholar : PubMed/NCBI
46	Gabrilovich DI and Nagaraj S: Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 9:162–174. 2009. View Article : Google Scholar : PubMed/NCBI
47	Gordon V, Bhadel S, Wunderlich W, et al: CDK9 regulates AR promoter selectivity and cell growth through serine 81 phosphorylation. Mol Endocrinol. 24:2267–2280. 2010. View Article : Google Scholar : PubMed/NCBI
48	Li LL, Hu ST, Wang SH, Lee HH, Wang YT and Ping YH: Positive transcription elongation factor b (P-TEFb) contributes to dengue virus-stimulated induction of interleukin-8 (IL-8). Cell Microbiol. 12:1589–1603. 2010. View Article : Google Scholar : PubMed/NCBI
49	Smallie T, Ricchetti G, Horwood NJ, Feldmann M, Clark AR and Williams LM: IL-10 inhibits transcription elongation of the human TNF gene in primary macrophages. J Exp Med. 207:2081–2088. 2010. View Article : Google Scholar : PubMed/NCBI
50	Holgersen K, Kvist PH, Hansen AK and Holm TL: Predictive validity and immune cell involvement in the pathogenesis of piroxicam-accelerated colitis in interleukin-10 knockout mice. Int Immunopharmacol. 21:137–147. 2014. View Article : Google Scholar : PubMed/NCBI