Tissue Angiotensin II During Progression or Ventricular Hypertrophy to Heart Failure in Hypertensive Rats; Differential Effects on PKCε and PKCβ

K. Inagaki, Y. Iwanaga, N. Sarai, Y. Onozawa, H. T akenaka, D. Mochly-Rosen and Y. Kihara. Tissue Angiotensin II During Progression of Ventricular Hypertrophy to Heart Failure in Hypertensive Rats; Differential Effects on PKCε and PKCβ. Journal of Molecular and Cellular Cardiology (2002) 34, 1377–1385. The protein kinase C (PKC) family has been implicated as second messengers in mechanosensitive modulation of cardiac hypertrophy. However, little information is available on the role of expression and activation of specific cardiac PKC isozymes during development of left ventricular hypertrophy (LVH) and failure (LVF). Dahl salt-sensitive rats fed an 8% salt diet developed systemic hypertension and concentric LVH at 11 weeks of age that is followed by left ventricle (LV) dilatation and global hypokinesis at 17 weeks. Among several PKC isozymes expressed in the LV myocardium, only PKCε showed a 94% increase at the LVH stage. At the LVF stage, however, PKCε returned to the control level, whereas PKCβI and βII increased by 158% and 155%, respectively. Hearts were studied at each stage using the Langendorff set-up, and a LV balloon was inflated to achieve an equivalent diastolic wall stress. Following mechanical stretch, PKCε was significantly activated in LVH myocardium in which tissue angiotensin II levels were increased by 59%. Pre-treatment with valsartan, an AT1-receptor blocker, abolished the stretch-mediated PKCε activation. Mechanical stretch no longer induced PKCε activation in LVF. Chronic administration of valsartan blunted the progression of LVF and inhibited the increase in PKCβ. Mechanosensitive PKCε activation is augmented and therefore may contribute to the development of compensatory hypertrophy. This effect was dependent on activation of tissue angiotensin II. However, this compensatory mechanism becomes inactive in LVF, where PKCβ may participate in the progression to cardiac dysfunction and LV remodeling.