Recombinant adeno-associated virus-mediated human kallikrein gene therapy protects against hypertensive target organ injuries through inhibiting cell apoptosis.
OBJECTIVE
Overexpression of human tissue kallikrein (HK), mediated by recombinant adeno-associated virus (rAAV), decreased blood pressure in spontaneous hypertensive rats (SHRs) and reduced injury to the heart, aorta and kidney. In this study, we used both an in vivo animal model and in vitro cell culture system to investigate whether rAAV-mediated HK gene therapy protects against organ damage by inhibiting cell apoptosis.


METHODS
rAAV encoding HK (rAAV-HK) or LacZ (rAAV-lacZ) were delivered as a control to spontaneously hypertensive rats (SHRs) and cultured human embryonic kidney (HEK) 293 cells.


RESULTS
Treatment with rAAV-HK decreased cell apoptosis in the target organs of SHRs and also inhibited lipopolysaccharide (LPS)-induced HEK 293 apoptosis. The rAAV-HK delivery system also increased the levels of apoptosis-inhibiting proteins bcl-2 and bcl-x(L), and decreased the level of Bax and the activity of caspase 3, two promoters of apoptosis. In addition to its role in the inhibition of apoptosis, rAAV-HK also activated the cell survival and proliferation signaling pathways ERK1/2 and PI3K/AKT.


CONCLUSIONS
rAAV-mediated HK gene delivery has multiple therapeutic possibilities for treating hypertension, not only by decreasing blood pressure, but also by directly inhibiting end-organ damage.
Yan
Jiang-tao
JT
Department of Internal Medicine and the Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China.
Wang
Tao
T
Wang
Dao-wen
DW
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000628:therapy*; D016234:Kallikrein-Kinin System / Q000502:physiology; D007610:Kallikreins / Q000235:genetics*; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics / Q000502:physiology
D048049:Extracellular Signal-Regulated MAP Kinases; D007610:Kallikreins; D053148:Caspase 3
J Virol. 1998 Mar;72(3):2224-32
9499080
J Biol Chem. 2005 Mar 4;280(9):8022-30
15611141
Biol Chem. 2006 Jun;387(6):665-75
16800727
Exp Physiol. 2005 May;90(3):291-8
15653716
Biochem Pharmacol. 2009 Jan 15;77(2):269-76
18938142
Nephrol Dial Transplant. 2006 Mar;21(3):624-33
16401625
Hypertension. 2002 Jan;39(1):75-80
11799082
Acta Pharmacol Sin. 2007 Dec;28(12):1898-906
18031602
Hypertension. 2001 Sep;38(3 Pt 2):581-7
11566935
Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):156-60
8552595
Circ Res. 2000 Aug 4;87(3):179-83
10926866
J Mol Cell Cardiol. 1997 Mar;29(3):859-70
9152847
Oncogene. 2008 Oct 20;27(48):6194-206
18931687
Hum Gene Ther. 2008 Apr;19(4):318-30
18402547
Circ Res. 1996 Oct;79(4):748-56
8831498
Clin Exp Pharmacol Physiol. 2008 Apr;35(4):489-93
18307747
Hypertension. 1995 Oct;26(4):642-8
7558225
Gene Ther. 2000 Jan;7(1):24-30
10680012
Int Immunopharmacol. 2008 Feb;8(2):148-54
18182218
Hypertension. 2001 Sep;38(3 Pt 2):543-8
11566928
Hypertension. 2003 Dec;42(6):1206-52
14656957
BMB Rep. 2008 Jan 31;41(1):11-22
18304445
Cardiovasc Res. 2003 Sep 1;59(3):549-62
14499856
J Pharmacol Exp Ther. 2007 Oct;323(1):210-6
17636004
Am J Physiol Heart Circ Physiol. 2002 May;282(5):H1635-41
11959625
FASEB J. 2000 May;14(7):991-8
10783154
Gene Ther. 2008 Jun;15(11):858-63
18418415
Acta Pharmacol Sin. 2008 Jul;29(7):808-14
18565278
Gene Ther. 2004 Sep;11(17):1342-50
15175642