RETRACTED: Prevention of renovascular and cardiac pathophysiological changes in hypertension by angiotensin II type 1 receptor antisense gene therapy

Abstract

Hypertension produces pathophysiological changes that are often responsible for the mortality associated with the disease. However, it is unclear whether normalizing blood pressure (BP) with conventional therapy is effective in reversing the pathophysiological damage. The duration and initiation of treatment, site of administration, and agent used all appear to inf luence the reversal of the pathophysiological alterations associated with hypertension. We have previously established that retrovirally mediated delivery of angiotensin II type 1 receptor antisense (AT 1 R-AS) attenuates the development of high BP in the spontaneously hypertensive (SH) rat model of human essential hypertension. Our objective was to determine whether this attenuation of high BP is associated with prevention of other pathophysiological changes induced by the hypertensive state. Intracardiac delivery of AT 1 R-AS in neonates prevented the development of hypertension in SH rats for at least 120 days. Contractile experiments demonstrated an impaired endothelium-dependent vascular relaxation (acetylcholine) and an enhanced contractile response to vasoactive agents (phenylephrine and KCl) in the SH rat renal vasculature. In addition, the voltage-dependent K ؉ current density, which is believed to contribute to smooth muscle resting membrane potential and basal tone, was decreased in renal resistance artery cells of the SH rat. AT 1 R-AS treatment prevented each of these renal vascular alterations. Finally, AT 1 R-AS delivery prevented the pathological alterations observed in the SH rat myocardium, including left ventricular hypertrophy, multifocal fibrosis, and perivascular fibrosis. These observations demonstrate that viral-mediated delivery of AT 1 R-AS attenuates the development of hypertension on a long term basis, and this is associated with prevention of pathophysiological changes in SH rats.The elevation of systemic blood pressure (BP) associated with hypertension is a risk factor for cardiovascular disease and renal failure. Often it is the pathophysiological alterations and impairments associated with hypertension that lessen life expectancy. Pharmacological intervention has been relatively successful in normalizing the elevation in BP. However, the assumption that reduction of BP will totally reverse hypertension-induced pathophysiological changes remains unclear (1-4).The duration of treatment, age at which the antihypertensive therapy is initiated, site of administration, and specific agent used all appear to influence the reversal of the pathophysiological alterations associated with the disease (5-7). In some instances, reversal of pathophysiological alterations may even be unfavorable, such as when regression of left ventricular hypertrophy and peripheral resistance occur in a disproportionate manner (8). Similarly, other reports have indicated that traditional antihypertensive agents can contribute to target organ injury by altering metabolic processes (i.e., hypercholesterolemia, glucose intolerance, hyperkalemia).A...

Heme Oxygenase-1 Gene Expression Modulates Angiotensin II–Induced Increase in Blood Pressure

“…[23][24][25][26] We also showed that the human HO-1 gene can be expressed in adult SHR by injecting the retroviral vector LSN-HHO-1 into newborns, 19 a method used by others, for example, to overexpress or suppress angiotensin receptors. 27 In a previous study, long-term expression of human HO-1 resulted in attenuation of hypertension in SHR. 19 The present study builds on the previous findings and further attempts to elucidate the mechanisms that may contribute to the effect of HO-1 expression on blood pressure.…”

Somatic gene therapy for hypertension

“…However, PCR analysis of the vector DNA showed that the virus had disappeared by 30 days indicating that the long-term effect was due to exposure to antisense for the AT 1 -R at a critical period. In all respects, the SHR had become as normal as their normotensive controls (16). Retroviruses are appropriate for dividing cells but are limited by their lack of effect in non-dividing cells and therefore are not suitable for hypertension therapy in adults.…”

Is Gene Therapy for Hypertension Possible?

“…10 -14 The vasoconstrictor gene inhibition strategy with AS in DNA in rAAV appears to be effective for reducing high BP in animal models of hypertension, including SHR, for at least 2 months. 26,42 Retrovirus delivery of AS AT 1 -R prevents hypertension from developing in young SHR 30,31 but may be limited to a developmental model because the vector infects only dividing cells. Eventually the development of these strategies could provide new antihypertensive options.…”

“…Nevertheless, this had beneficial effects, and a repeat of the experiment showed that the AS AT 1 -R had prevented the development not only of hypertension but also of cardiac fibrosis. 31 Retroviruses are appropriate for dividing cells but are limited by their lack of effect in nondividing cells and therefore cannot be used for hypertension therapy in adults, although they may be useful for cardiomyopathy, restenosis, and vascular remodeling.…”