Intramuscular delivery of rAAV-mediated kallikrein gene reduces hypertension and prevents cardiovascular injuries in model rats.

AIM: The overexpression of the human tissue kallikrein (HK) gene can reduce blood pressure and ameliorate the secondary syndromes associated with hypertension in animal models. The current study was designed to investigate hypotensive effect of intramuscular delivery of HK gene. METHODS: We generated an recombinant adeno-associated virus (rAAV) vector expressing human tissue kallikrein under the control of a cytomegalovirus promoter and administered the rAAV-HK vector to a spontaneously hypertensive rat model at a dose of 1 x 10(10) virons/rat through intramuscular injection. RESULTS: A persistent, high-level expression of HK post-gene delivery was confirmed by ELISA. The systolic blood pressure in the rats receiving rAAV-LacZ and saline increased from 171.3 mmHg to 182.3 mmHg 28 weeks' post injection. In contrast, the delivery of the HK gene by AAV vectors attenuated the increase of the systolic blood pressure in the treated group. The systolic blood pressure was only slightly lowered (from a level of 174 mmHg to 170.5 mmHg) post-vector administration. The difference in blood pressure between the treated group and the control groups is statistically significant at 12.6 mmHg. The hypotensive effect of rAAV-HK persisted until the end of the testing period. In addition, a significant amelioration of cardiovascular hypertrophy, renal injury, and collagen depositions in the rAAV-HK-treated animals were also observed. CONCLUSION: All the effects are comparable with those of intravenous delivery. Therefore, the intramuscular administration of rAAV-HK may be used in gene therapy for hypertension.

Cystatin C, associated with hemorrhagic and ischemic stroke, is a strong predictor of the risk of cardiovascular events and death in Chinese.

BACKGROUND AND PURPOSE: Cystatin C, a serum measure of renal function, has been reported as a strong predictor of risk of death and cardiovascular events in elderly people. We investigated the association between cystatin C and first-ever stroke and evaluated the predictive value of cystatin C in cardiovascular events and death from all causes based on the outcomes of a 5-year follow-up. METHODS: We recruited 293 stroke patients (199 cases of cerebral infarction, 94 cases of cerebral hemorrhage) and 894 controls. For each measure, the study population was divided into quintiles. RESULTS: Total plasma cystatin C levels were significantly higher in patients than controls. Higher cystatin C levels were directly associated with a higher risk of stroke. As compared with the first (lowest) quintile, the hazard ratios (and 95% CIs) for stroke were as follows: second quintile, 1.97 (1.07 to 3.64); third quintile, 2.71 (1.50 to 4.90); fourth quintile, 3.79 (2.12 to 6.75); fifth quintile, 6.38 (3.60 to 11.32). Follow-up of the patients and controls also showed that high cystatin C levels were associated with high prevalence of cardiovascular events or death from all causes. CONCLUSIONS: Elevated cystatin C levels were independently associated with both ischemic and hemorrhagic stroke, and cystatin C was a strong predictor for the risk of cardiovascular events and death.