In diabetes and hypertension, the induction of increased transforming growth factor- (TGF-) activity due to glucose and angiotensin II is a significant factor in the development of fibrosis and organ failure. We showed previously that glucose and angiotensin II induce the latent TGF- activator thrombospondin-1 (TSP1). Because activation of latent TGF- is a major means of regulating TGF-, we addressed the role of TSP1-mediated TGF- activation in the development of diabetic cardiomyopathy exacerbated by abdominal aortic coarctation in a rat model of type 1 diabetes using a peptide antagonist of TSP1-dependent TGF- activation. This surgical manipulation elevates initial blood pressure and angiotensin II. The hearts of these rats had increased TSP1, collagen, and TGF- activity, and cardiac function was diminished. A peptide antagonist of TSP1-dependent TGF- activation prevented progression of cardiac fibrosis and improved cardiac function by reducing TGF- activity. These data suggest that TSP1 is a significant mediator of fibrotic complications of diabetes associated with stimulation of the renin-angiotensin system, and further studies to assess the blockade of TSP1-dependent TGF- activation as a potential antifibrotic therapeutic strategy are warranted. (Am J Pathol
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...
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