Effect of combined treatment with rosuvastatin and protein kinase Cβ2 inhibitor on angiogenesis following myocardial infarction in diabetic rats

Huang,Dong; Wang,Fa-Bin; Guo,Ming; Li,Shuai; Yan,Mei-Ling; Yu,Tao; Wei,Meng; Li,Jing-Bo

doi:10.3892/ijmm.2014.2043

Effect of combined treatment with rosuvastatin and protein kinase Cβ2 inhibitor on angiogenesis following myocardial infarction in diabetic rats

Authors:
- Dong Huang
- Fa-Bin Wang
- Ming Guo
- Shuai Li
- Mei-Ling Yan
- Tao Yu
- Meng Wei
- Jing-Bo Li
View Affiliations

Affiliations: Division of Cardiology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai Jiaotong University School of Medicine, State Key Discipline Division, Shanghai 200233, P.R. China, Division of Cardiology, Tengzhou Central People's Hospital, Tengzhou, Shandong 277500, P.R. China
Published online on: December 18, 2014 https://doi.org/10.3892/ijmm.2014.2043
Pages: 829-838

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

The aim of the present study was to investigate the effects of combined treatment with rosuvastatin and LY333531, a selective protein kinase C (PKC)β2 inhibitor, on angiogenesis under hyperglycemic conditions. Human umbilical vein endothelial cells (HUVECs) cultured in medium containing a normal or high concentration of glucose (33.3 mmol/l) were treated with rosuvastatin (0.1 µmol/l) alone or in combination with LY333531 (10 nmol/l). HUVEC migration and tube formation were assessed. Furthermore, rats with streptozotocin-induced diabetes were randomly divided into groups and treated with either rosuvastatin alone (5 mg/kg/day) or in combination with LY333531 (10 mg/kg/day) for 4 weeks following the induction of myocardial infarction (MI). Echocardiographic patterns, the extent of myocardial fibrosis, capillary density in myocardial tissue, the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), as well as the expression levels of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-α (HIF‑1α) were assessed. The results from the in vitro experiment revealed that the tube-forming and migration ability of the HUVECs exposed to high-glucose medium was significantly improved in the group treated with the combination of rosuvastatin and LY333531. In vivo, the combination of rosuvastatin and LY333531 significantly improved left ventricular function, reduced the extent of myocardial fibrosis and increased myocardial capillary density compared to treatment with rosuvastatin alone. In addition, the expression levels of VEGF, and Akt and eNOS phosphorylation were significantly higher in the group exposed to the combination treatment than in the group treated with rosuvastatin alone. The results of the present study indicate that, compared to treatment with rosuvastatin alone, combined treatment with rosuvastatin and LY333531 promotes a greater level of angiogenesis in diabetic rats with MI. This effect is likely mediated through the upregulation of the VEGF‑dependent Akt/eNOS signaling pathway.

View Figures

View References

1	Nordlie MA, Wold LE and Kloner RA: Genetic contributors toward increased risk for ischemic heart disease. J Mol Cell Cardiol. 39:667–679. 2005. View Article : Google Scholar : PubMed/NCBI
2	Habib GB, Heibig J, Forman SA, Brown BG, Roberts R, Terrin ML, et al: Influence of coronary collateral vessels on myocardial infarct size in humans: results of phase I Thrombolysis in Myocardial Infarction (TIMI) trial: the TIMI Investigators. Circulation. 83:739–746. 1991. View Article : Google Scholar : PubMed/NCBI
3	Samuel SM, Thirunavukkarasu M, Penumathsa SV, Koneru S, Zhan L, Maulik G, et al: Thioredoxin-1 gene therapy enhances angiogenic signaling and reduces ventricular remodeling in infarcted myocardium of diabetic rats. Circulation. 121:1244–1255. 2010. View Article : Google Scholar : PubMed/NCBI
4	Boodhwani M, Sodha NR, Mieno S, Xu SH, Feng J, Ramlawi B, et al: Functional, cellular, and molecular characterization of the angiogenic response to chronic myocardial ischemia in diabetes. Circulation. 116(11 Suppl): 131–137. 2007. View Article : Google Scholar
5	Martin A, Komada MR and Sane DC: Abnormal angiogenesis in diabetes mellitus. Med Res Rev. 23:117–145. 2003. View Article : Google Scholar
6	Shweiki D, Itin A, Soffer D and Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 359:843–845. 1992. View Article : Google Scholar : PubMed/NCBI
7	Hammes HP, Lin J, Bretzel RG, Brownlee M and Breier G: Upregulation of the vascular endothelial growth factor/vascular endothelial growth factor receptor system in experimental background diabetic retinopathy of the rat. Diabetes. 47:401–406. 1998. View Article : Google Scholar : PubMed/NCBI
8	Cooper ME, Vranes D, Youssef S, Stacker SA, Cox AJ, Rizkalla B, et al: Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes. 48:2229–2239. 1999. View Article : Google Scholar : PubMed/NCBI
9	Chou E, Suzuma I, Way KJ, Opland D, Clermont AC, Naruse K, et al: Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic States: a possible explanation for impaired collateral formation in cardiac tissue. Circulation. 105:373–379. 2002. View Article : Google Scholar : PubMed/NCBI
10	Mellor H and Parker PJ: The extended protein kinase C super-family. Biochem J. 332:281–292. 1998.
11	Geraldes P and King GL: Activation of protein kinase C isoforms and its impact on diabetic complications. Circ Res. 106:1319–1331. 2010. View Article : Google Scholar : PubMed/NCBI
12	Inoguchi T, Battan R, Handler E, Sportsman JR, Heath W and King GL: Preferential elevation of protein kinase C isoform II and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation. Proc Natl Acad Sci USA. 89:11059–11063. 1992. View Article : Google Scholar
13	Sheetz MJ and King GL: Molecular understanding of hyperglycemia’s adverse effects for diabetic complications. JAMA. 288:2579–2588. 2002. View Article : Google Scholar : PubMed/NCBI
14	Wei L, Yin Z, Yuan Y, Hwang A, Lee A, Sun D, et al: A PKC-beta inhibitor treatment reverses cardiac microvascular barrier dysfunction in diabetic rats. Microvasc Res. 80:158–165. 2010. View Article : Google Scholar : PubMed/NCBI
15	Naruse K, Rask-Madsen C, Takahara N, Ha SW, Suzuma K, Way KJ, et al: Activation of vascular protein kinase C-beta inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance. Diabetes. 55:691–698. 2006. View Article : Google Scholar : PubMed/NCBI
16	He Z and King GL: Protein kinase C beta isoform inhibitors: a new treatment for diabetic cardiovascular diseases. Circulation. 110:7–9. 2004. View Article : Google Scholar : PubMed/NCBI
17	Sata M, Nishimatsu H, Osuga J, Tanaka K, Ishizaka N, Ishibashi S, et al: Statins augment collateral growth in response to ischemia but they do not promote cancer and atherosclerosis. Hypertension. 43:1214–1220. 2004. View Article : Google Scholar : PubMed/NCBI
18	Erbs S, Beck EB, Linke A, Adams V, Gielen S, Kränkel N, et al: High-dose rosuvastatin in chronic heart failure promotes vasculogenesis, corrects endothelial function, and improves cardiac remodeling–results from a randomized, double-blind, and placebo-controlled study. Int J Cardiol. 146:56–63. 2011. View Article : Google Scholar
19	Siddiqui AJ, Gustafsson T, Fischer H, Widegren U, Hao X, Mansson-Broberg A, et al: Simvastatin enhances myocardial angiogenesis induced by vascular endothelial growth factor gene transfer. J Mol Cell Cardiol. 37:1235–1244. 2004.PubMed/NCBI
20	Miura S, Matsuo Y and Saku K: Transactivation of KDR/Flk-1 by the B2 receptor induces tube formation in human coronary endothelial cells. Hypertension. 41:1118–1123. 2003. View Article : Google Scholar : PubMed/NCBI
21	Nakamura S, Chikaraishi Y, Tsuruma K, Shimazawa M, Hara H, et al: Ruboxistaurin, a PKCbeta inhibitor, inhibits retinal neovascularization via suppression of phosphorylation of ERK1/2 and Akt. Exp Eye Res. 90:137–145. 2010. View Article : Google Scholar
22	Shi F, Wang YC, Zhao TZ, Zhang S, Du TY, Yang CB, et al: Effects of simulated microgravity on human umbilical vein endothelial cell angiogenesis and role of the PI3K-Akt-eNOS signal pathway. PLoS One. 7:e403652012. View Article : Google Scholar : PubMed/NCBI
23	Huang FY, Mei WL, Li YN, Tan GH, Dai HF, Guo JL, et al: Toxicarioside A inhibits tumor growth and angiogenesis: involvement of TGF-β/endoglin signaling. PLoS One. 7:e503512012. View Article : Google Scholar
24	Xin P, Zhu W, Li J, Ma S, Wang L, Liu M, et al: Combined local ischemic postconditioning and remote perconditioning recapitulate cardioprotective effects of local ischemic preconditioning. Am J Physiol Heart Circ Physiol. 298:H1819–H1831. 2010. View Article : Google Scholar : PubMed/NCBI
25	Derumeaux G, Mulder P, Richard V, Chagraoui A, Nafeh C, Bauer F, et al: Tissue Doppler imaging differentiates physiological from pathological pressure-overload left ventricular hypertrophy in rats. Circulation. 105:1602–1608. 2002. View Article : Google Scholar : PubMed/NCBI
26	Tang JM, Wang JN, Zhang L, Zheng F, Yang JY, Kong X, et al: VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovasc Res. 91:402–411. 2011. View Article : Google Scholar : PubMed/NCBI
27	Xie J, Lu W, Gu R, Dai Q, Zong B, Ling L, et al: The impairment of ILK related angiogenesis involved in cardiac maladaptation after infarction. PLoS One. 6:e241152011. View Article : Google Scholar : PubMed/NCBI
28	Yu T, Zhu W, Gu B, Li S, Wang F, Liu M, et al: Simvastatin attenuates sympathetic hyperinnervation to prevent atrialfibrillation during the postmyocardial infarction remodeling process. J Appl Physiol. 113:1937–1944. 2012. View Article : Google Scholar
29	Chilian WM, Penn MS, Pung YF, Dong F, Mayorga M, Ohanyan V, et al: Coronary collateral growth - back to the future. J Mol Cell Cardiol. 52:905–911. 2012. View Article : Google Scholar : PubMed/NCBI
30	Hoole SP, White PA, Read PA, Heck PM, West NE, O’Sullivan M, et al: Coronary collaterals provide a constant scaffold effect on the left ventricle and limit ischemic left ventricular dysfunction in humans. J Appl Physiol. 112:1403–1409. 2012. View Article : Google Scholar : PubMed/NCBI
31	Fujita M, Ikemoto M, Kishishita M, Otani H, Nohara R, Tanaka T, et al: Elevated basic fibroblast growth factor in pericardial fluid of patients with unstable angina. Circulation. 94:610–613. 1996. View Article : Google Scholar : PubMed/NCBI
32	Chilian WM, Mass HJ, Williams SE, Layne SM, Smith EE, Scheel KW, et al: Microvascular occlusions promote coronary collateral growth. Am J Physiol. 258:H1103–H1111. 1990.PubMed/NCBI
33	Abaci A, Oguzhan A, Kahraman S, Eryol NK, Unal S, Arinc H, et al: Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation. 99:2239–2242. 1999. View Article : Google Scholar : PubMed/NCBI
34	Yarom R, Zirkin H, Stammler G and Rose AG: Human coronary microvessels in diabetes and ischaemia. Morphometric study of autopsy material. J Pathol. 166:265–270. 1992. View Article : Google Scholar : PubMed/NCBI
35	Dubois S, Madec AM, Mesnier A, Armanet M, Chikh K, Berney T, et al: Glucose inhibits angiogenesis of isolated human pancreatic islets. J Mol Endocrinol. 45:99–105. 2010. View Article : Google Scholar : PubMed/NCBI
36	Elewa HF, El-Remessy AB, Somanath PR and Fagan SC: Diverse effects of statins on angiogenesis: new therapeutic avenues. Pharmacotherapy. 30:169–176. 2010. View Article : Google Scholar : PubMed/NCBI
37	Zaitone SA and Abo-Gresha NM: Rosuvastatin promotes angiogenesis and reverses isoproterenol-induced acute myocardial infarction in rats: role of iNOS and VEGF. Eur J Pharmacol. 691:134–142. 2012. View Article : Google Scholar : PubMed/NCBI
38	Liu Y, Lei S, Gao X, Mao X, Wang T, Wong GT, et al: PKCβ inhibition with ruboxistaurin reduces oxidative stress and attenuates left ventricular hypertrophy and dysfunction in rats with streptozotocin-induced diabetes. Clin Sci (Lond). 122:161–173. 2012. View Article : Google Scholar
39	Kelly DJ, Zhang Y, Hepper C, Gow RM, Jaworski K, Kemp BE, et al: Protein kinase C beta inhibition attenuates the progression of experimental diabetic nephropathy in the presence of continued hypertension. Diabetes. 52:512–518. 2003. View Article : Google Scholar : PubMed/NCBI
40	Wang F, Huang D, Zhu W, Li S, Yan M, Wei M, et al: Selective inhibition of PKCβ2 preserves cardiac function after myocardial infarction and is associated with improved angiogenesis of ischemic myocardium in diabetic rats. Int J Mol Med. 32:1037–1046. 2013.PubMed/NCBI
41	Ikeda A, Matsushita S and Sakakibara Y: Inhibition of protein kinase Cβ ameliorates impaired angiogenesis in type I diabetic mice complicating myocardial infarction. Circ J. 76:943–949. 2012. View Article : Google Scholar
42	Ma YX, Li WH and Xie Q: Rosuvastatin inhibits TGF-beta1 expression and alleviates myocardial fibrosis in diabetic rats. Pharmazie. 68:355–358. 2013.PubMed/NCBI
43	Palaniyandi SS, Ferreira JC, Brum PC and Mochly-Rosen D: PKCβII inhibition attenuates myocardial infarction induced heart failure and is associated with a reduction of fibrosis and pro-inflammatory responses. J Cell Mol Med. 15:1769–1777. 2011. View Article : Google Scholar :