Direct gene delivery of human tissue kallikrein reduces blood pressure in spontaneously hypertensive rats.

Wang, Cindy; Chao, Lee; Chao, Julie

doi:10.1172/jci117847

Cited by 135 publications

(78 citation statements)

References 42 publications

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“…Recently, more attention has been paid to gene therapy for hypertension, which would produce a long-lasting effect without taking pills daily. The tested genes include those coding for atrial natriuretic peptide (Lin et al, 1997a), endothelial nitric oxide synthase (Lin et al, 1997b) and hKLK1 (Wang et al, 1995), among which hKLK1 gene has been proved to be more potential to achieve hypotensive effect. Here we present additional evidence that both hKLK1 gene delivery and rK1 administration can be used as alternative strategies for treating human hypertension.…”

Section: Introductionmentioning

confidence: 99%

Prolonged hypotensive effect of human tissue kallikrein gene delivery and recombinant enzyme administration in spontaneous hypertension rats

Sun

Zhang²,

Wang³

et al. 2004

Exp Mol Med

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A bstractTo evaluate the feasibility of treating hypertension by hum an tissue kallikrein gene (K LK 1) delivery and by enzym e (rK1) adm inistration, tw o recombinant vectors expressing KLK1 cDNA were constructed for gene delivery (pcDNA-KLK1) and recombinant enzym e preparation (pO V-KLK1). Expression of the pcDNA-KLK1 vector in COS-1 cells was confirm ed by im m unofluorescence and in spontaneous hypertension rats (SHR) by enzymatic detection. Follow ing intram uscular or intravenous injection w ith the pcDNA-KLK1 vector, systolic pressure of SHR w as significantly decreased, w hich lasted for 20 d to two m onths depending on dose, route and/or tim e of injection. Egg w hite containing recom binant hK1 was prepared by injection of egg-laying hens w ith the oviduct-specific expression vector pO V-KLK1 and adm inistered into SHR via oral gavage. Follow ing adm inistration, systolic pressure of the SHR w as decreased to that of norm al rats, which lasted for 3-5 d depending on the dosage used. These data suggest that both hKLK1 gene delivery and recom binant enzym e adm inistration can be used as alternative strategies for treating hum an hypertension. K eyw ords: gene delivery; human tissue kallikrein; hypotensive effect; recombinant enzyme administration

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Section: Introductionmentioning

confidence: 99%

Prolonged hypotensive effect of human tissue kallikrein gene delivery and recombinant enzyme administration in spontaneous hypertension rats

Sun

Zhang²,

Wang³

et al. 2004

Exp Mol Med

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“…254 Potentially, other factors, such as dietary potassium intake, may interact to modify associations with urinary kallikrein. 255 Whereas gene delivery of human tissue kallikrein reduced blood pressure in spontaneously hypertensive rats, 256 mice made deficient in either the bradykinin receptor-2 or tissue kallikrein were not hypertensive. 257 Further work will be required to provide further clarification of the role, if any, of the renal kallikrein-kinin system in hypertension.…”

Section: ␣-Adducin (Add1)mentioning

confidence: 99%

Genetics of hypertension

Hopkins

Hunt

2003

Genetics in Medicine

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Hypertension is the most prevalent cardiovascular disorder. In the 1999 to 2000 NHANES survey, the prevalence of hypertension progressively increased from 7.2% in those aged 18 to 39 to 30.1% in 40 to 59 year olds and 65.4% in those 60 and older. 1 Risk of both coronary atherosclerosis and stroke increase exponentially as blood pressure rises (see Fig. 1). 2 Although the relative risk for stroke increases more rapidly than coronary disease, at any pressure, the absolute risk for coronary disease is considerably greater than for stroke. An insight into this finding comes from autopsy studies that show that the carotid and intracerebral vascular beds are relatively protected from atherosclerosis as compared to the coronary circulation, particularly at lower blood pressures (see Fig. 2). 3,4 Probably the major means whereby hypertension accelerates atherosclerosis is through pressure-driven convection of LDL and other atherogenic particles into the arterial intima. 5-8 Indeed, without at least arterial pressures, atherosclerosis does not exist in the vascular tree 9 even in patients with homozygous familial hypercholesterolemia. 10,11 Increased turbulence (a rare occurrence in the human circulatory system) does not increase atherosclerosis. Rather, higher sheer stress is a strong stimulus for release of nitric oxide that locally decreases risk of atherosclerosis. Focal areas of low sheer stress are at inherently increased risk of atherosclerotic disease (such as the coronary arteries where flow stops during each systole). 12 Interestingly, in most studies, stroke risk has been affected little by serum total cholesterol, 13,14 although some recent studies identify clear associated risk. 15 At least some association with all standard cardiovascular risk factors should be expected, not only because thromboembolic stroke may be caused by carotid tree atherosclerosis, but because aortic plaques have been strongly implicated as an embolic source for ischemic stroke. 16 -18 Hypertension is not just a risk factor for atherosclerosis. High blood pressure can have direct adverse effects on arteries, arterioles, and the heart, resulting in potentially severe consequences beyond the more common manifestations of myocardial infarction and atherothrombotic stroke. Even modestly elevated blood pressure is a major risk factor for congestive heart failure. 19,20 Hypertension is a major contributor to left ventricular hypertrophy, a major risk factor for sudden death independent of other risk factors. 21,22 Hypertension can lead progressively to arterial and arteriolar hypertrophy, arteriosclerosis and arteriolosclerosis, and with very high pressures to fibrinoid change and fibrinoid necrosis in arterioles. These latter changes can result in lumen compromise of arterioles resulting in lacunar stroke, Charcot-Bouchard aneurysms, glomerulosclerosis and nephrosclerosis, and ultimately malignant hypertension in the kidney and retinal ischemia and blindness. Risk of intracerebral hemorrhage is increased 33-fold at stage 3 or higher pre...

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“…The extent of BP reduction is dependent on the dose of injected DNA. 12 Human tissue kallikrein 1 (KLK1) protein (EC 3.4.21.35), a key serine protease, is encoded by KLK1 gene located on chromosome 19q13.2-13.4. The KLK1 generates Lys-bradykinin by specific proteolysis of kininogen-1.…”

Section: Introductionmentioning

confidence: 99%

Effects of protein coding polymorphisms in the kallikrein 1 gene on baseline blood pressure and antihypertensive response to irbesartan in Chinese hypertensive patients

Jiang

et al. 2010

J Hum Hypertens

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The aim of this study was to determine the association between coding variants in the human tissue kallikrein 1 (KLK1) gene and baseline blood pressure (BP) and antihypertensive response to irbesartan treatment in Chinese hypertensive patients. A total of 1061 hypertensives were recruited and received daily oral dosage of 150 mg irbesartan for 4 weeks. Predose BPs, BPs and blood irbesartan concentrations at postdose on the 28th day were all measured. Common functional singlenucleotide polymorphisms (SNPs) in the KLK1 gene were genotyped. On the basis of the HapMap data of Han Chinese in the Beijing population, two non-synonymous polymorphisms with minor allele frequency40.1, SNP rs5517 (Glu162Lys) and rs5516 (Gln121Glu), were selected. Those with GG genotype in the rs5516 locus had higher average baseline systolic BP (SBP) than CC subjects (b±s.e.: 5.0±2.3, P ¼ 0.033); and no associations of rs5517 with baseline BP (diastolic BP (DBP) and SBP) and BP responses, or rs5516 with baseline DBP and BP response were observed. In a haplotype-based association test for the KLK1 gene, the Haplo-special score analyses identified that haplotype AG was marginally associated with SBP response (specific score: 1.75 for P ¼ 0.08), but not with DBP response. We did not find any associations between haplotypes (GC and AC) and BP responses. The Haplo-GLM analyses showed that, compared with haplotype GC subjects, the subjects with haplotype AG had a marginally greater SBP response (adjusted b ± s.e.: 1.81 ± 0.97, P ¼ 0.06), but DBP response did not differ. This study suggests that rs5516 in the KLK1 gene may be involved in the development of essential hypertension and in the regulation of SBP-lowering response to irbesartan in Chinese hypertensives.

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Direct gene delivery of human tissue kallikrein reduces blood pressure in spontaneously hypertensive rats.

Cited by 135 publications

References 42 publications

Prolonged hypotensive effect of human tissue kallikrein gene delivery and recombinant enzyme administration in spontaneous hypertension rats

Prolonged hypotensive effect of human tissue kallikrein gene delivery and recombinant enzyme administration in spontaneous hypertension rats

Genetics of hypertension

Effects of protein coding polymorphisms in the kallikrein 1 gene on baseline blood pressure and antihypertensive response to irbesartan in Chinese hypertensive patients

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