Therapeutic targeting of mitochondrial superoxide in hypertension.
BACKGROUND
Superoxide (O2(-) ) has been implicated in the pathogenesis of many human diseases including hypertension; however, commonly used antioxidants have proven ineffective in clinical trials. It is possible that these agents are not adequately delivered to the subcellular sites of superoxide production.


OBJECTIVE
Because the mitochondria are important sources of reactive oxygen species, we postulated that mitochondrial targeting of superoxide scavenging would have therapeutic benefit.


RESULTS
In this study, we found that the hormone angiotensin (Ang II) increased endothelial mitochondrial superoxide production. Treatment with the mitochondria-targeted antioxidant mitoTEMPO decreased mitochondrial O2(-), inhibited the total cellular O2(-), reduced cellular NADPH oxidase activity, and restored the level of bioavailable NO. These effects were mimicked by overexpressing the mitochondrial MnSOD (SOD2), whereas SOD2 depletion with small interfering RNA increased both basal and Ang II-stimulated cellular O2(-). Treatment of mice in vivo with mitoTEMPO attenuated hypertension when given at the onset of Ang II infusion and decreased blood pressure by 30 mm Hg following establishment of both Ang II-induced and DOCA salt hypertension, whereas a similar dose of nontargeted TEMPOL was not effective. In vivo, mitoTEMPO decreased vascular O2(-), increased vascular NO production and improved endothelial-dependent relaxation. Interestingly, transgenic mice overexpressing mitochondrial SOD2 demonstrated attenuated Ang II-induced hypertension and vascular oxidative stress similar to mice treated with mitoTEMPO.


CONCLUSIONS
These studies show that mitochondrial O2(-) is important for the development of hypertension and that antioxidant strategies specifically targeting this organelle could have therapeutic benefit in this and possibly other diseases.
Dikalova
Anna E
AE
Division of Cardiology, Emory University School of Medicine, 1639 Pierce Dr, Atlanta, GA 30322, USA.
Bikineyeva
Alfiya T
AT
Budzyn
Klaudia
K
Nazarewicz
Rafal R
RR
McCann
Louise
L
Lewis
William
W
Harrison
David G
DG
Dikalov
Sergey I
SI
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D002417:Cattle; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods*; D042783:Endothelial Cells; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D013482:Superoxide Dismutase / Q000096:biosynthesis*; D013481:Superoxides / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D000975:Antioxidants; D003497:Cyclic N-Oxides; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2; C003959:TEMPO
Endocrinology. 2003 Jun;144(6):2179-83
12746271
Circulation. 1997 Feb 4;95(3):588-93
9024144
Neurochem Res. 2003 Oct;28(10):1563-74
14570402
Am J Nephrol. 2007;27(6):545-53
17785964
Aging Cell. 2004 Feb;3(1):13-6
14965350
Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):762-8
17272743
J Pharmacol Sci. 2006;100(5):370-90
16651701
Aging Cell. 2007 Dec;6(6):783-97
17925005
JAMA. 2008 Nov 12;300(18):2123-33
18997197
Free Radic Biol Med. 2008 Nov 1;45(9):1340-51
18760347
Hypertension. 2007 Apr;49(4):717-27
17296874
Arterioscler Thromb Vasc Biol. 2000 Oct;20(10):2175-83
11031201
Biochem Pharmacol. 2005 Aug 1;70(3):343-54
15963955
Proc Natl Acad Sci U S A. 2005 Dec 27;102(52):19126-31
16365298
Hypertension. 2009 Aug;54(2):322-8
19581509
J Biol Chem. 1996 Oct 18;271(42):26026-31
8824242
Circ Res. 2008 Feb 29;102(4):488-96
18096818
Am J Clin Nutr. 2009 Aug;90(2):429-37
19491386
Am J Physiol Regul Integr Comp Physiol. 2008 Dec;295(6):R1858-65
18922960
Hypertension. 2009 Aug;54(2):338-44
19506101
Free Radic Biol Med. 2009 Feb 1;46(3):329-38
19026738
Circ Res. 2007 Mar 2;100(4):460-73
17332437
Hypertension. 2006 Jan;47(1):81-6
16344366
Cardiology. 2005;103(3):137-41
15665536
Adv Drug Deliv Rev. 2000 Mar 30;41(2):235-50
10699318
Circulation. 2005 Oct 25;112(17):2668-76
16230485
Kidney Int. 2005 Jul;68(1):179-87
15954907
Biochem Biophys Res Commun. 1997 Jan 3;230(1):54-7
9020059
Methods Enzymol. 1996;264:484-509
8965721
Free Radic Biol Med. 2006 Sep 1;41(5):810-7
16895801
Circ Res. 2002 Sep 6;91(5):406-13
12215489
Arterioscler Thromb Vasc Biol. 2001 Apr;21(4):489-95
11304462
Hypertension. 1995 May;25(5):1111-5
7737724
Free Radic Biol Med. 2005 May 15;38(10):1278-95
15855047
Cardiol Clin. 2003 Aug;21(3):289-302
14621446
Free Radic Biol Med. 2006 Oct 15;41(8):1191-6
17015165
Exp Gerontol. 2006 Jul;41(7):653-7
16677792
J Clin Invest. 2003 Apr;111(8):1201-9
12697739
J Renin Angiotensin Aldosterone Syst. 2003 Jun;4(2):51-61
12806586
Clin Cardiol. 1997 Nov;20(11 Suppl 2):II-11-7
9422847
Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2462-72
16766635
Free Radic Biol Med. 2005 Sep 1;39(5):567-83
16085176
Methods Enzymol. 2005;396:597-610
16291267
Antioxid Redox Signal. 2007 Nov;9(11):1825-36
17854275
J Appl Physiol (1985). 2007 Jan;102(1):255-60
17023572
Am J Physiol Regul Integr Comp Physiol. 2009 Feb;296(2):R208-16
19073907