Since the inhibition of renin-angiotensin system can prevent or regress left ventricular hypertrophy (LVH) in animal models and clinical patients with hypertension, angiotensin II type 1A receptor (AT1AR)-mediated signaling has been considered as one of the important transcriptional pathways in the development of cardiac hypertrophy. However, there is a recent evidence that AT2R, not AT1AR, is essential for LVH in chronic angiotensin II (Ang II)-induced hypertension. To address whether AT1AR-mediated signaling plays an important role in the development of pressure overload LVH, we evaluated LV weight and hemodynamic parameters before and after transverse aortic constriction (TAC) in the wild-type (WT) and AT1AR knockout (KO) mice. Although LV systolic pressure (83.2짹10.0 mmHg, n=5) of KO mice was lower than WT mice (90.0짹5.0 mmHg, n=7), the average increase in LV systolic pressure by TAC was similar (WT, 42.0 mmHg; KO, 41.8 mmHg) and LV end-diastolic pressure, LV +dP/dtmax, and heart rate was not different between two groups. LV weight/BW ratio was markedly increased not only in WT (4.17짹0.28 mg/g, n=9) but also in KO mice (4.16짹0.43 mg/g, n=8) at 2 weeks after TAC, and the degree of LVH was almost identical between two groups (WT, 34.5%; KO, 36.8% increase in LV weight/BW ratio). We further investigated the interaction of mitogen-activated protein kinase (MAPK) in the pressure overload LVH. Myocardial ERK 1/2 and JNK activity was not changed significantly after TAC in both groups, whereas p38-MAPK activity was increased in a same degree after pressure overloading to LV in both groups. Interstitial and perivascular fibrosis developed by pressure overload to LV in KO mice was significantly less than that of WT mice. Taken together, pressure overload by TAC induced LVH in KO mice as well as WT mice without any hemodynamic differences or changes in MAPK activity. These results suggest that Ang II-mediated signaling is involved in the development of cardiac fibrosis and LVH could be induced by pressure overload in the in vivo heart without AT1AR-mediated signaling.
|
