Role of Angiotensin II Type 1A Receptor-Mediated Signaling in the Development of Pressure Overload-Induced Left Ventricular Hypertrophy and Fibrosis

BACKGROUND AND OBJECTIVES: The roles of angiotensin II (Ang II) in the regulation of heart function under normal and pathological conditions have been well documented, with its biological actions mainly mediated via the Ang II type 1A receptor (AT(1A)R). Since the inhibition of the renin-angiotensin system can prevent or regress left ventricular hypertrophy (LVH) with hypertension, AT(1A)R-mediated signaling is considered one of the important transcriptional pathways in the development of cardiac hypertrophy. SUBJECTS AND METHODS: To address whether AT(1A)R-mediated signaling plays an important role in the development of pressure overload-induced LVH and fibrosis, the physiological, biochemical, hemodynamic and histopathological parameters were evaluated before and after transverse aortic constriction (TAC) in wild-type (WT) and AT(1A)R knockout (KO) mice. RESULTS: Although the LV systolic pressure (83.2+/-10.0 mmHg, n=5) of the KO mice was lower than that (90.0+/-5.0 mmHg, n=7) of the WT mice, there was no difference in the increase in the LV systolic pressure between the WT and KO mice (WT, 42.0 mmHg; KO, 41.8 mmHg). Also, there was no difference between the baseline LV-to-body weight (LVW/BW) ratio between the two groups (WT, 3.10+/-0.21 mg/g; KO 3.04+/-0.21 mg/g). Two weeks after TAC, the degree of increase in the LVW/BW ratio was markedly increased in both the WT (4.17+/-0.28 mg/g, n=9) and KO mice (4.16+/-0.43 mg/g, n=8), which were almost identical (WT, 34.5%; KO, 36.8%). There were no significant differences in the LV end-diastolic pressure, LV+dP/dt(max), and heart rate between the two groups. The ERK44/42 and p38-MAPK activities in the LV were markedly increased by TAC in both groups, but that of JNK was not. Interstitial and perivascular fibrosis developed in both groups following TAC. However, the degree of increased fibrosis was significantly attenuated in the KO mice. CONCLUSION: These results suggest AT(1A)R-mediated signaling is not indispensable for the development of pressure overload-induced LVH, and provides new insights into the development of novel therapeutic strategies for cardiac hypertrophy.

Perivascular Delivery of Paclitaxel with F-127 Pluronic Gel Inhibits Neointimal Hyperplasia in a Rat Carotid Artery Injury Model

BACKGROUND AND OBJECTIVES: The local delivery of drugs to the arterial wall represents a strategy for the treatment of fibroproliferative vascular disease. Paclitaxel has been shown to inhibit vascular smooth muscle cell proliferation and migration, which contribute to neointimal formation. This study tested whether the perivascular delivery of paclitaxel can prevent neointimal formation in a rat carotid artery injury model. MATERIALS AND METHODS: The ability of locally-administered paclitaxel to prevent the neointimal hyperplastic response was tested by incorporating 10 microgram paclitaxel into 40% F-127 pluronic gel, which was then applied to the adventitial surface of the rat carotid artery immediately following balloon injury. Fourteen days after angioplasty, the neointimal growth was compared between paclitaxel- (n=12) and pluronic gel only treated (control group, n=11) rats. RESULTS: The paclitaxel-treated group showed significant neointimal formation reductions compared to the control group (0.10+/-0.05 versus 0.21+/-0.05 mm2, p<0.05). The perivascular application of paclitaxel produced a highly localized pattern of neointimal growth inhibition in the arterial cross-section. Although 10 microgram paclitaxel showed no significant cytotoxicity, 20 microgram paclitaxel (n=3) demonstrated cytotoxicity, with medial cell drop out in the region of application. CONCLUSION: We have demonstrated that the local extravascular application of 40% F-127 pluronic gel containing paclitaxel provides an effective mechanism for inhibiting the proliferative response to vascular injury in the rat. The cellular response to paclitaxel is highly focal. Locally sustained delivery of paclitaxel, as little as 10 microgram, was effective in preventing neointimal growth, without destroying medial wall smooth muscle cells.