Mutation of the protein kinase i alpha leucine zipper domain produces hypertension and progressive left ventricular hypertrophy: A novel mouse model of age-dependent hypertensive heart disease

Hypertensive heart disease causes significant mortality in older patients, yet there is an incomplete understanding of molecular mechanisms that regulate age-dependent hypertensive left ventricular hypertrophy (LVH). Therefore, we tested the hypothesis that the cGMP-dependent protein kinase G I alpha (PKGIα;) attenuates hypertensive LVH by evaluating the cardiac phenotype in mice with selective mutations of the PKGIα; leucine zipper domain. These leucine zipper mutant (LZM) mice develop basal hypertension. Compared with wild-type controls, 8-month-old adult LZM mice developed increased left ventricular end-diastolic pressure but without frank LVH. In advanced age (15 months), the LZM mice developed overt pathological LVH. These findings reveal a role of PKGIα; in normally attenuating hypertensive LVH. Therefore, mutation of the PKGIα; LZ domain produces a clinically relevant model for hypertensive heart disease of aging.