Ribonucleic acid interference knockdown of interleukin 6 attenuates cold-induced hypertension.
The purpose of this study was to determine the role of the proinflammatory cytokine interleukin (IL) 6 in cold-induced hypertension. Four groups of male Sprague-Dawley rats were used (6 rats per group). After blood pressure was stabilized, 3 groups received intravenous delivery of adenoassociated virus carrying IL-6 small hairpin RNA (shRNA), adenoassociated virus carrying scrambled shRNA, and PBS, respectively, before exposure to a cold environment (5 degrees C). The last group received PBS and was kept at room temperature (25 degrees C, warm) as a control. Adenoassociated virus delivery of IL-6 shRNA significantly attenuated cold-induced elevation of systolic blood pressure and kept it at the control level for < or =7 weeks (length of the study). Chronic exposure to cold upregulated IL-6 expression in aorta, heart, and kidneys and increased macrophage and T-cell infiltration in kidneys, suggesting that cold exposure increases inflammation. IL-6 shRNA delivery abolished the cold-induced upregulation of IL-6, indicating effective silence of IL-6. Interestingly, RNA interference knockdown of IL-6 prevented cold-induced inflammation, as evidenced by a complete inhibition of tumor necrosis factor-alpha expression and leukocyte infiltration by IL-6 shRNA. RNA interference knockdown of IL-6 significantly decreased the cold-induced increase in vascular superoxide production. It is noted that IL-6 shRNA abolished the cold-induced increase in collagen deposition in the heart, suggesting that inflammation is involved in cold-induced cardiac remodeling. Cold exposure caused glomerular collapses, which could be prevented by knockdown of IL-6, suggesting an important role of inflammation in cold-induced renal damage. In conclusion, cold exposure increased IL-6 expression and inflammation, which play critical roles in the pathogenesis of cold-induced hypertension and cardiac and renal damage.
Crosswhite
Patrick
P
Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126-0901, USA.
Sun
Zhongjie
Z
D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D001795:Blood Pressure Determination; D003080:Cold Temperature; D016001:Confidence Intervals; D000229:Dependovirus; D004195:Disease Models, Animal; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D011336:Probability; D012313:RNA / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D015850:Interleukin-6; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013481:Superoxides; D012313:RNA
Ageing Res Rev. 2009 Jan;8(1):36-42
18930842
J Cardiovasc Pharmacol. 2005 Dec;46(6):735-9
16306795
Front Biosci (Elite Ed). 2010 Jan 01;2:495-503
20036896
Cardiol Rev. 2009 Sep-Oct;17(5):216-21
19690472
J Hum Hypertens. 2005 Jun;19(6):457-62
15759024
Hypertension. 2006 Oct;48(4):711-6
16940225
JAMA. 1997 Sep 24;278(12):1012-4
9307350
Hypertension. 2001 Feb;37(2 Pt 2):376-80
11230303
Cardiovasc Hematol Disord Drug Targets. 2008 Dec;8(4):252-60
19075635
Curr Opin Nephrol Hypertens. 2005 Mar;14(2):125-31
15687838
Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2106-13
16100037
Hypertension. 2003 Feb;41(2):322-7
12574102
Curr Pharm Des. 2006;12(13):1623-35
16729874
J Am Soc Nephrol. 1995 Jul;6(1):95-101
7579076
Hypertension. 1998 Jun;31(6):1317-23
9622148
Ann N Y Acad Sci. 1997 Mar 15;813:682-8
9100955
Circulation. 2004 Aug 31;110(9):1103-7
15313950
Curr Opin Nephrol Hypertens. 2009 Mar;18(2):122-7
19430333
Schweiz Med Wochenschr. 1993 Dec 18;123(50):2363-9
8272812
J Hypertens. 1996 Dec;14(12):1421-5
8986924
Am J Hypertens. 2008 Dec;21(12):1288-91
18846043
Am J Public Health. 1982 Mar;72(3):261-5
7058966
Am J Hypertens. 2008 Oct;21(10):1152-6
18670418
Inflamm Res. 2009 Aug;58(8):473-82
19271152
J Neurosci. 2008 Dec 17;28(51):13957-66
19091984
Clin Exp Hypertens A. 1982;4(3):341-54
7074993
Trends Pharmacol Sci. 2008 Jul;29(7):367-74
18579222
Circ Res. 2009 Jul 31;105(3):223-30
19644057
J Hypertens. 2002 May;20(5):871-7
12011647
Curr Opin Nephrol Hypertens. 2006 Mar;15(2):152-8
16481882
Mol Cell Biochem. 2000 Mar;206(1-2):105-12
10839200
Biochem Pharmacol. 2005 Jan 15;69(2):255-65
15627478
Regul Pept. 2010 Jan 8;159(1-3):110-6
19748527
Hypertension. 2009 Oct;54(4):810-7
19635988
Can J Physiol Pharmacol. 1995 Jan;73(1):72-8
7600456
J Clin Invest. 2008 Nov;118(11):3537-45
18982160
Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1880-7
18296563
Curr Opin Rheumatol. 2009 May;21(3):224-30
19365268
J Appl Physiol (1985). 1989 Feb;66(2):741-9
2708203
J Am Coll Cardiol. 1999 Jun;33(7):1916-9
10362193
J Biol Chem. 2002 May 24;277(21):18710-7
11907026
Clin Sci (Lond). 2007 Jun;112(7):375-84
17324119
Hypertension. 1997 Jan;29(1 Pt 2):374-80
9039130
J Am Soc Nephrol. 2008 Mar;19(3):433-42
18256353
Vasc Med. 2007 Feb;12(1):23-7
17451090
Physiol Behav. 1999 Jan 1-15;65(4-5):879-84
10073495
Physiol Genomics. 2010 Apr 1;41(2):120-6
20086041
Stroke. 2004 Jul;35(7):1726-31
15143297
Am J Hypertens. 2002 Feb;15(2 Pt 1):176-80
11863254
Gene Ther. 2006 Jul;13(14):1097-103
16554840