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AAV‐mediated vascular smooth muscle‐specific knockdown of Cav1.2 as a long‐term anti‐hypertensive therapy
Author(s) -
Pang Li,
Sonkusare Swapnil,
Thakali Keshari,
Melchert Russell,
Roberto Kerrey,
Palade Philip
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.932.4
Subject(s) - gene knockdown , vascular smooth muscle , genetic enhancement , medicine , gene silencing , small hairpin rna , angiotensin ii , adeno associated virus , rna interference , endocrinology , pharmacology , microbiology and biotechnology , blood pressure , chemistry , biology , gene , smooth muscle , vector (molecular biology) , rna , biochemistry , recombinant dna
Hypertension is a chronic disease, but currently all antihypertensive drugs have relatively short half‐lives. To improve patient compliance, we hypothesize that AAV‐mediated Ca v 1.2 siRNA gene therapy which selectively reduces the abnormal expression of Ca v 1.2 in vascular smooth muscle cells (VSMCs) will provide a long‐term antihypertensive effect. We previously reported a miRNA‐based shRNA expression cassette driven by a VSMC‐specific enhancer/promoter significantly reduced Cav1.2 expression and function in cultured VSMCs but not in non‐VSMCs tested. In this study, we subcloned the VSMC‐specific siRNA expression cassettes into an AAV vector and injected the viruses into angiotensin II‐induced hypertensive mice by tail vein injection. Compared to control virus‐treated mice, blood pressure of AAV/Cav1.2 siRNA‐treated mice decreased ~30 mm Hg and remained reduced for = 4 weeks. L‐type Ca currents from isolated mesenteric artery VSMCs significantly decreased in AAV/Cav1.2 siRNA‐treated mice (‐4.58±1.51 pA/pF vs. ‐10.96±1.89 pA/pF in control virus‐treated mice, p<0.05). Expression of Cav1.2 siRNA was VSMC‐selective since GFP (an expression marker, driven by the same promoter as the Cav1.2 siRNA) mRNA was only detected in arteries, but not in heart, brain, or liver. Conclusion AAV‐mediated VSMC‐specific knockdown of Ca v 1.2 may provide a long‐term therapy for hypertension. Supported by NIH HL63903.