Angiotensin inhibition decreases progression of advanced atherosclerosis and stabilizes established atherosclerotic plaques.

Although increased extracellular matrix (ECM) is pathogenic in a variety of chronic tissue injuries, reduced and/or disrupted ECM may be detrimental in atherosclerosis and rather destabilize existing atherosclerotic lesions. This study therefore assessed the effects of angiotensin II (AngII) antagonism on ECM components of advanced atherosclerosis. Twenty-four-week-old apolipoprotein E-deficient mice were treated with the AngII antagonist losartan for 12 wk. Controls received water or hydralazine. AngII antagonism significantly reduced progression of established atherosclerosis, whereas hydralazine showed no benefit despite similar decrease in BP. Although there was no difference in the macrophage component, AngII antagonism increased the relative collagen portion of the lesions; lessened elastin fragmentation, increased the total elastin content of the aorta; and reduced the mRNA and activity/protein of the elastolytic proteases, cathepsin S, and metalloproteinase-9. Extracellular elastin degradation by cultured smooth muscle cells (SMC) was reduced by losartan, as was SMC invasion through an elastin gel barrier. Thus, AngII antagonism lessens progression of atherosclerosis, increases collagen, and preserves elastin components of ECM within the vascular lesions, which, at least in part, is modulated by effects on SMC. These effects not only decrease further expansion of advanced lesions but also stabilize the established atherosclerotic plaques and may underlie the decreased incidence of acute cardiovascular events that are observed in patients in whom AngII antagonism is begun after atherosclerosis is already established.

Transiently heightened angiotensin II has distinct effects on atherosclerosis and aneurysm formation in hyperlipidemic mice.

Experimentally sustained increase in angiotensin II (AngII) promotes tissue destruction in various cardiovascular disorders. We examined whether transiently heightened AngII affects subsequent atherosclerosis and aneurysm formation. AngII or saline was administered for 2 weeks to apolipoprotein E (apoE)-deficient mice. Mice were sacrificed at the end of the 2-week infusion or 6- or 14 weeks later. Short-term AngII did not affect atherosclerosis immediately following the infusion or 6 weeks later. By contrast, 14 weeks after infusion there was remarkably more atherosclerosis in previously AngII-exposed mice. Preceding the build up of atherosclerotic lesions, AngII-exposure increased mRNA expression and immunostaining of monocyte chemoattractant protein-1 (MCP-1) and its receptor, CCR2. This was followed by greater macrophage-positivity in AngII-exposed aortae. In contrast to the delayed effects on atherosclerosis, 20% of mice were found to have abdominal aneurysms at the end of AngII-exposure. This effect was not contingent on blood pressure. Moreover, despite amplification in atherosclerosis following AngII, no aneurysms were found 14 weeks later. Our studies reveal that even transient exposure to AngII primes the vessel for subsequent amplification of atherosclerosis which involves activation of MCP-1/CCR2 and influx of macrophages into the nascent atherosclerotic plaque. By contrast, transient AngII-exposure causes prompt aneurysm formation that does not parallel atherosclerosis and disappears even in the face of progressively greater atherosclerotic lesions.

Antiatherogenic effects of angiotensin receptor antagonism in mild renal dysfunction.

Angiotensin II (Ang II) increases atherosclerotic cardiovascular disease. Renal damage that is characterized by activation of Ang II markedly potentiates the risk for atherosclerosis, even in the setting of subtle renal impairment. Therefore, whether antagonism of Ang II actions can modify atherosclerosis in a model of mild renal impairment was examined. Apolipoprotein E-deficient spontaneously hyperlipidemic mice underwent uninephrectomy (UNx) or sham operation (sham) followed by treatment with Ang II receptor antagonist losartan or hydralazine for 12 wk. While UNx did not increase the serum creatinine levels, BP and lipids were higher in UNx mice than in age-matched sham controls with intact kidneys. UNx caused a dramatic increase in the extent and the number of atherosclerotic lesions together with greater macrophage-positive area and more disruption in the elastin component of the extracellular matrix versus sham. Ang II antagonism dramatically decreased the UNx-induced acceleration in atherosclerosis in association with decreased macrophage content, linked to decreased macrophage migration in vitro with losartan but not with hydralazine. Aortae of mice treated with Ang II antagonism had fewer elastin breaks together with less immunostaining for the powerful elastolytic enzyme cathepsin S. None of these benefits was observed in the hydralazine-treated mice despite equivalent reduction in BP. These findings support an important role for endogenous Ang II in accelerated atherosclerosis in renal dysfunction and offer a therapeutic intervention with particular benefit in this setting through mechanisms that include reduced vascular macrophage infiltration and preservation of the elastin component of extracellular matrix.

Hepatocyte growth factor gene therapy retards the progression of chronic obstructive nephropathy.

BACKGROUND: Unilateral ureteral obstruction (UUO) is characterized by progressive tubular atrophy and interstitial fibrosis. Rupture of the balance between cell proliferation and apoptosis plays a critical role in renal atrophy. Hepatocyte growth factor (HGF) is a cytokine function on cell survival and tissue regeneration. We studied the effects and possible mechanisms of HGF gene therapy on tubular cell survival and anti-fibrosis in chronic obstructed nephropathy. METHODS: An in vivo transfection procedure of repeatedly transducing skeletal muscles with the HGF gene using liposomes containing the hemagglutinating virus of Japan (HVJ liposome) was tested on UUO rats. Expression of HGF and c-Met were examined by in situ hybridization, ELISA, or immunohistochemical staining. Interstitial fibrosis and macrophage infiltration were evaluated by Masson's Trichrome staining, alpha-smooth muscle actin and ED-1 immunostaining. Cell survival indices including proliferating cell nuclear antigen (PCNA), Bcl-2, Bcl-xL and Bax were measured by immunohistochemistry and Western blots. Apoptosis was determined by the TUNEL method. RESULTS: After HVJ-HGF gene transfer, endogenous HGF and c-Met were up-regulated in UUO kidneys. Renal fibrosis, macrophage infiltration and tubular atrophy were suppressed both at day 14 and 28 after UUO (P < 0.05 or 0.01). Tubular cell proliferation was activated while apoptosis was inhibited, especially at the late stage of UUO. Bcl-2 was enhanced in the HGF-transfected UUO rats, while no changes of Bcl-xL and Bax were found. CONCLUSIONS: In vivo HGF gene transfection retards the progression of chronic obstructed nephropathy and protects tubular cell survival in the long-term UUO model. Bcl-2 rather than Bcl-xL or Bax may contribute to the anti-apoptotic function of HGF.