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Recombinant adeno-associated virus-mediated human kallikrein gene therapy protects against hypertensive target organ injuries through inhibiting cell apoptosis.

Yan JT, Wang T, Wang DW - Acta Pharmacol. Sin. (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine and the Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China.

ABSTRACT

Aim: 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.

Conclusion: 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.

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Related in: MedlinePlus

The kallikrein/kinin system inhibits apoptosis by modulating the bcl-2 protein family. Protein expression levels in the tissue samples were detected by Western blot analysis (A). Blots were scanned and the relative expression levels, as determined by densitometry, were normalized to total β-actin as shown in the histogram (B, C, D). Kallikrein gene delivery significantly increased the protein levels of bcl-2, and bcl-xL two anti-apoptotic proteins, and decreased the protein level of Bax, a pro-apoptotic protein. cP<0.01 vs rAAV-LacZ group.
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fig3: The kallikrein/kinin system inhibits apoptosis by modulating the bcl-2 protein family. Protein expression levels in the tissue samples were detected by Western blot analysis (A). Blots were scanned and the relative expression levels, as determined by densitometry, were normalized to total β-actin as shown in the histogram (B, C, D). Kallikrein gene delivery significantly increased the protein levels of bcl-2, and bcl-xL two anti-apoptotic proteins, and decreased the protein level of Bax, a pro-apoptotic protein. cP<0.01 vs rAAV-LacZ group.

Mentions: In order to understand the mechanisms underlying the anti-apoptotic effects of HK gene delivery on the target organs of SHRs, we examined the expression levels of different genes in the bcl-2 protein family using Western blotting. Kallikrein gene delivery significantly increased the protein levels of bcl-2 and bcl-xl, two known anti-apoptosis proteins, and decreased the protein level of Bax, a pro-apoptosis protein (Figure 3). These observations suggested that the overexpression of kallikrein gene inhibited hypertension-induced cell apoptosis by modulating the expression of bcl-2 protein family members.


Recombinant adeno-associated virus-mediated human kallikrein gene therapy protects against hypertensive target organ injuries through inhibiting cell apoptosis.

Yan JT, Wang T, Wang DW - Acta Pharmacol. Sin. (2009)

The kallikrein/kinin system inhibits apoptosis by modulating the bcl-2 protein family. Protein expression levels in the tissue samples were detected by Western blot analysis (A). Blots were scanned and the relative expression levels, as determined by densitometry, were normalized to total β-actin as shown in the histogram (B, C, D). Kallikrein gene delivery significantly increased the protein levels of bcl-2, and bcl-xL two anti-apoptotic proteins, and decreased the protein level of Bax, a pro-apoptotic protein. cP<0.01 vs rAAV-LacZ group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4007182&req=5

fig3: The kallikrein/kinin system inhibits apoptosis by modulating the bcl-2 protein family. Protein expression levels in the tissue samples were detected by Western blot analysis (A). Blots were scanned and the relative expression levels, as determined by densitometry, were normalized to total β-actin as shown in the histogram (B, C, D). Kallikrein gene delivery significantly increased the protein levels of bcl-2, and bcl-xL two anti-apoptotic proteins, and decreased the protein level of Bax, a pro-apoptotic protein. cP<0.01 vs rAAV-LacZ group.
Mentions: In order to understand the mechanisms underlying the anti-apoptotic effects of HK gene delivery on the target organs of SHRs, we examined the expression levels of different genes in the bcl-2 protein family using Western blotting. Kallikrein gene delivery significantly increased the protein levels of bcl-2 and bcl-xl, two known anti-apoptosis proteins, and decreased the protein level of Bax, a pro-apoptosis protein (Figure 3). These observations suggested that the overexpression of kallikrein gene inhibited hypertension-induced cell apoptosis by modulating the expression of bcl-2 protein family members.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine and the Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, China.

ABSTRACT

Aim: 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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus