Journal List > J Korean Soc Hypertens > v.19(4) > 1089818

Lee, Hong, Jeong, Joo, Park, Ahn, Yu, and Lim: Effects of a PPAR-γ (Peroxisome Proliferator-Activated Receptor-gamma) Activator on Flow-Mediated Brachial Artery Dilation and Circulating Level of microRNA-21 in Hypertensive Type 2 Diabetic Patients

ABSTRACT

Background:

Endothelial dysfunction has been documented in patients with type 2 diabetes especially when combined with hypertension. We prospectively investigated the effects of pioglitazone in improving endothelial function in hypertensive type 2 diabetic patients during the 6-month follow-up.

Methods:

Hypertensive type 2 diabetic patients were randomly assigned to pioglitazone (n = 25) or placebo (n = 25). Primary endpoint was to compare changes in brachial artery flow-mediated dilation (baFMD) between the 2 groups during the 6-month follow-up. Secondary endpoints were to compare changes in the circulating levels of microRNA-17, -21, 92a, -126, and -145 which have been known as indicators of endothelial cell migration and atherosclerosis progression during the 6-month follow-up. Inflammatory markers such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), high-sensitive C-reactive protein, adiponectin, soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were compared during the follow-up.

Results:

The prevalences of risk factors such as hyperlipidemia, smoking, stroke, and family history of coronary artery disease did not show significant differences between the 2 groups. Increases in baFMD (0.33 ± 0.34 mm vs. 0.02 ± 0.25 mm, p < 0.05, respectively) and in the level of circulating microRNA-21 (0.23 ± 0.05 vs. -0.06 ± 0.04, p < 0.05, respectively) were significantly greater in the pioglitazone group when compared to the placebo group during the 6-month follow-up. No significant differences in the prevalences of new onset heart failure, fracture, and bladder cancer were noted during the follow-up between the 2 groups. Decreases in the levels of inflammatory marker such as IL-6 (-2.54 ± 2.32 pg/mL vs. -1.34 ± 2.12 pg/mL, p < 0.05, respectively), TNF-α (-1.54 ± 1.51 pg/mL vs. 0.14 ± 1.12 pg/mL, p < 0.05, respectively), sICAM-1 (-39 ± 52 ng/mL vs. 6 ± 72 ng/mL, p < 0.05, respectively), and sVCAM-1 (-154 ± 198 ng/mL vs. -11 ± 356 ng/mL, p < 0.05, respectively) were significantly greater in the pioglitazone group compared to the placebo group during the follow-up.

Conclusions:

In hypertensive type 2 diabetic patients, pioglitazone may increase baFMD and circulatory microRNA-21 and decrease inflammatory cytokines including IL-6, TNF-α, sICAM-1, and sVCAM-1.

References

1. Moody WE, Edwards NC, Madhani M, Chue CD, Steeds RP, Ferro CJ. et al. Endothelial dysfunction and cardiovascular disease in early-stage chronic kidney disease: cause or association? Atherosclerosis. 2012; 223:86–94.
2. Weiss TW, Arnesen H, Seljeflot I. Components of the interleukin-6 transsignalling system are associated with the metabolic syndrome, endothelial dysfunction and arterial stiffness. Metabolism. 2013; 62:1008–13.
crossref
3. Hong SJ, Ahn TH, Baek SH, Cho WH, Jeon HK, Kwan J, et al. Comparison of efficacy and tolerability of amlodipine orotate versus amlodipine besylate in adult patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 8-week follow-up, noninferiority trial. Clin Ther. 2006; 28:537–51.
crossref
4. Bakris G, Briasoulis A, Dahlof B, Jamerson K, Weber MA, Kelly RY, et al. Comparison of benazepril plus amlodipine or hydrochlorothiazide in high-risk patients with hypertension and coronary artery disease. Am J Cardiol. 2013; 112:255–9.
crossref
5. Lee DC, Sui X, Church TS, Lavie CJ, Jackson AS, Blair SN. Changes in fitness and fatness on the development of cardiovascular disease risk factors hypertension, metabolic syndrome, and hypercholesterolemia. J Am Coll Cardiol. 2012; 59:665–72.
6. Hong SJ, Choi SC, Ahn CM, Park JH, Kim JS, Lim DS. Telmisartan reduces neointima volume and pulse wave velocity 8 months after zotarolimus-eluting stent implantation in hypertensive type 2 diabetic patients. Heart. 2011; 97:1425–32.
crossref
7. Hong SJ, Kim ST, Kim TJ, Kim EO, Ahn CM, Park JH, et al. Cellular and molecular changes associated with inhibitory effect of pioglitazone on neointimal growth in patients with type 2 diabetes after zotarolimus-eluting stent implantation. Arterioscler Thromb Vasc Biol. 2010; 30:2655–65.
crossref
8. Jin DK, Lee SJ. How much do we lower the blood pressure in hypertensive patients with diabetes? J Korean Soc Hypertens. 2011; 17:10–6.
9. Mizoguchi M, Tahara N, Tahara A, Nitta Y, Kodama N, Oba T, et al. Pioglitazone attenuates atherosclerotic plaque inflammation in patients with impaired glucose tolerance or diabetes a prospective, randomized, comparator-controlled study using serial FDG PET/CT imaging study of carotid artery and ascending aorta. JACC Cardiovasc Imaging. 2011; 4:1110–8.
10. Hsiao FY, Hsieh PH, Huang WF, Tsai YW, Gau CS. Risk of bladder cancer in diabetic patients treated with rosiglitazone or pioglitazone: a nested case-control study. Drug Saf. 2013; 36:643–9.
crossref
11. Ferwana M, Firwana B, Hasan R, Al-Mallah MH, Kim S, Montori VM, et al. Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies. Diabet Med. 2013; 30:1026–32.
crossref
12. Aubert RE, Herrera V, Chen W, Haffner SM, Pendergrass M. Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab. 2010; 12:716–21.
crossref
13. Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ. 2009; 180:32–9.
crossref
14. Fichtlscherer S, Zeiher AM, Dimmeler S. Circulating microRNAs: biomarkers or mediators of cardiovascular diseases? Arterioscler Thromb Vasc Biol. 2011; 31:2383–90.
15. Meigs JB, Hu FB, Rifai N, Manson JE. Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. JAMA. 2004; 291:1978–86.
crossref
16. Libby P, Plutzky J. Inflammation in diabetes mellitus: role of peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-gamma agonists. Am J Cardiol. 2007; 99:27B–40B.
17. Hallberg C, Rosengren B, Camejo G. Effect of fatty acid on HDL-mediated efflux of cholesterol in THP-1 uman macrophages and human monocytes-derived macrophages. Chem Phys Lipids. 2005; 136:132–3.
18. Jin RC, Min PK, Chan SY. MicroRNA in the diseased pulmonary vasculature: implications for the basic scientist and clinician. J Korean Soc Hypertens. 2013; 19:1–16.
crossref
19. Jazbutyte V, Thum T. MicroRNA-21: from cancer to cardiovascular disease. Current Drug Targets. 2010; 11:926–35.
crossref
20. Cheng Y, Zhang C. MicroRNA-21 in cardiovascular disease. J Cardiovasc Transl Res. 2010; 3:251–5.
crossref
21. Kaluza D, Kroll J, Gesierich S, Manavski Y, Boeckel JN, Doebele C, et al. Histone deacetylase 9 promotes angiogenesis by targeting the antiangiogenic microRNA-17-92 cluster in endothelial cells. Arterioscler Thromb Vasc Biol. 2013; 33:533–43.
crossref
22. Wu W, Xiao H, Laguna-Fernandez A, Villarreal G. Jr., Wang KC, Geary GG, et al. Flow-Dependent Regulation of Kruppel-Like Factor 2 Is Mediated by MicroRNA-92a. Circulation. 2011; 124:633–41.
23. Wei Y, Nazari-Jahantigh M, Neth P, Weber C, Schober A. MicroRNA-126, -145. and -155: a therapeutic triad in athero-sclerosis? Arterioscler Thromb Vasc Biol. 2013; 33:449–54.
24. Maachi M, Pieroni L, Bruckert E, Jardel C, Fellahi S, Hainque B, et al. Systemic low-grade inflammation is related to both circulating and adipose tissue TNF alpha, leptin and IL-6 levels in obese women. Int J Obesity. 2004; 28:993–7.
25. You SH, Kim BS, Hong SJ, Ahn CM, Lim DS. The effects of pioglitazone in reducing atherosclerosis progression and neo-intima volume in type 2 diabetic patients: prospective randomized study with volumetric intravascular ultrasonography analysis. Korean Circ J. 2010; 40:625–31.
crossref
26. Hong SJ, Park CG, Seo HS, Kim JW, Rha SW, Oh DJ. Decrease in plasma adiponectin concentrations in patients with variant angina and acute coronary syndrome. Am J Cardiol. 2005; 95:61a–2a.
27. Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M, et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest. 2001; 107:1255–62.
crossref

Fig. 1.
Comparison of changes in brachial artery flow-mediated dilatation during the 6-month follow-up between the pioglitazone and control groups.
jksh-19-99f1.tif
Fig. 2.
(A) MicroRNA-21 increased significantly only in the pioglitazone group during the 6-month F/U, and (B) significant correlation was found between the changes in microRNA-21 and changes in brachial artery flow-mediated dilatation. (C) No significant differences were found with changes in microRNA-17, -92a, -126, and -145. baFMD, brachial artery flow-mediated dilation; F/U, follow-up.
jksh-19-99f2.tif
Table 1.
Baseline patient characteristics
Variable Pioglitazone group (n = 25) Control group (n = 25) p-value
Age (yr) 61.4 ± 12.4 59.5 ± 11.8 0.345
Male sex 16 (64.0) 14 (56.0) 0.564
Body mass index (kg/m2) 24.8 ± 4.1 24.1 ± 3.0 0.394
Risk factors
Hyperlipidemia 8 (32.0) 7 (28.0) 0.758
Current smoking 8 (32.0) 10 (40.0) 0.556
Family history of CAD 2 (8.0) 3 (12.0) 1.000
Past history of TIA or stroke 1 (4.0) 2 (8.0) 1.000
Insulin use 4 (16.0) 5 (20.0) 1.000
No. of hypertensive medication (2) ≥ 12 (48.0) 13 (52.0) 0.777
Hypertension medication
ACE inhibitor 4 (16.0) 3 (12.0) 1.000
Angiotensin receptor blocker 8 (32.0) 9 (36.0) 0.765
Beta blocker 3 (12.0) 2 (8.0) 1.000
Calcium channel blocker 6 (24.0) 8 (32.0) 0.529
Diuretics 6 (24.0) 5 (20.0) 0.733
LVEF (%) 61.1 ± 8.6 62.1 ± 9.1 0.881

Values are presented as mean ± standard deviation or number (%). The body mass index is the weight in kilograms divided by the square of the height in meters.

CAD, coronary artery disease; TIA, transient ischemic attack; ACE, angiotensin converting enzyme; LVEF, left ventricular ejection fraction.

Table 2.
Changes in brachial artery flow-mediated dilatation during the 6-month follow-up
Variable Pioglitazone group (n = 25) Control group (n = 25)
Baseline After 6 months Baseline After 6 months
Brachial artery diameter at rest (mm) 4.47 ± 0.58 4.51 ± 0.49 4.59 ± 0.59 4.57 ± 0.57
Flow-mediated dilatation (mm) 4.58 ± 0.58 4.91 ± 0.43*, 4.71 ± 0.59 4.73 ± 0.58
Changes from at rest (mm) 0.11 ± 0.06 0.40 ± 0.08*, 0.12 ± 0.07 0.16 ± 0.07
Changes from baseline (mm) 0.33 ± 0.34 0.02±0.25

* p < 0.05 compared with baseline.

p < 0.05 compared with the control group.

Table 3.
Changes in the level of inflammatory markers during the 6-month follow-up
Variable Pioglitazone group (n = 25) Control group (n = 25)
Baseline After 6 months Baseline After 6 months
Interleukin-6 (pg/mL) 3.91 ± 3.12 1.45 ± 1.10* 3.56 ± 3.21 2.23 ± 1.71*
Changes from baseline (pg/mL) -2.54 ± 2.32 -1.34 ± 2.12
Tumor necrosis factor-α (pg/mL) 5.71 ± 4.19 4.16 ± 2.56* 5.16 ± 3.41 4.99 ± 3.11
Changes from baseline (pg/mL) -1.54 ± 1.51 0.14 ± 1.12
High-sensitive C-reactive protein (mg/L) 4.89 ± 4.11 1.80 ± 1.57* 5.11 ± 4.22 1.89 ± 1.81*
Changes from baseline (mg/L) -3.09 ± 3.01 -3.21 ± 2.98
Adiponectin (μ g/mL) 5.29 ± 4.17 6.76 ± 4.14* 5.55 ± 3.85 6.49 ± 4.66*
Changes from baseline (μ g/mL) 1.47 ± 0.89 0.98 ± 0.88
sICAM-1 (ng/mL) 430 ± 154 391 ± 133* 416 ± 131 422 ± 172
Changes from baseline (ng/mL) -39 ± 52 6 ± 72
sVCAM-1 (ng/mL) 1107 ± 344 954 ± 328* 1088 ± 429 1077 ± 401
Changes from baseline (ng/mL) -154 ± 198 -11 ± 356

Values are presented as mean ± standard deviation.

sICAM-1, soluble intercellular adhesion molecule-1; sVCAM-1, soluble vascular cell adhesion molecule-1.

* p < 0.05 compared with baseline.

p < 0.05 compared with the control group.

Table 4.
Changes in the level of lipid profiles during the 6-month follow-up
Variable Pioglitazone group (n = 25) Control group (n = 25)
Baseline After 6 months Baseline After 6 months
Total cholesterol (mg/dL) 220 ± 54 144 ± 41* 215 ± 44 141 ± 32*
Changes from baseline (mg/dL) -76 ± 62 -75 ± 43
Low density lipoprotein cholesterol (mg/dL) 143 ± 73 73 ± 53* 146 ± 108 77 ± 39*
Changes from baseline (mg/dL) -70 ± 39 -68 ± 42
High density lipoprotein cholesterol (mg/dL) 44 ± 27 46 ± 18 40 ± 22 45 ± 12
Changes from baseline (mg/dL) 2 ± 9 4 ± 7
Triglyceride (mg/dL) 127 ± 71 110 ± 94 123 ± 74 113 ± 69
Changes from baseline (mg/dL) -16 ± 70 -10 ± 59

Values are presented as or mean ± standard deviation.

* p < 0.05 compared with baseline.

p < 0.05 compared with the control group.

Table 5.
Comparison of adverse clinical events between the 2 groups during the 6-month follow-up
Variable Pioglitazone group (n = 25) Control group (n = 25) p-value
Death 0 (0.0) 0 (0.0) NA
Myocardial infarction 0 (0.0) 1 (4.0) 1.000
New onset CHF 1 (4.0) 0 (0.0) 1.000
Fracture 1 (4.0) 0 (0.0) 1.000
Stroke 0 (0.0) 0 (0.0) NA
Bladder cancer 0 (0.0) 0 (0.0) NA

Values are presented as number (%).

CHF, congestive heart failure; NA, not available.

TOOLS
Similar articles