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_1AR). Since the inhibition of the renin-angiotensin system can prevent or regress left ventricular hypertrophy (LVH) with hypertension, AT_1AR-mediated signaling is considered one of the important transcriptional pathways in the development of cardiac hypertrophy.

To address whether AT_1AR-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_1AR knockout (KO) mice.

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.

These results suggest AT_1AR-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.