Proteasome inhibition promotes regression of left ventricular hypertrophy

Current research in left ventricular hypertrophy (LVH) has largely focused on its progression and therapeutic mechanisms to prevent or slow its development. Few studies have centered on the regression or treatment of existing LVH. Nuclear factor-kappaB (NF-kappaB) is an inflammatory transcription factor that has been shown to be involved in LVH development. We hypothesized that proteasome-mediated NF-kappaB inhibition would prevent the development of LVH and promote its regression. A murine model of reversible hypertrophy was employed by administering isoproterenol (Iso) subcutaneously for 7-14 days. The proteasome inhibitor, PS-519, was delivered both concurrently and after Iso treatment. LVH was quantified by heart weight-to-body weight ratios, histology, transthoracic echocardiography, and hypertrophic gene expression. After 7 days of Iso treatment, all measures indicated successful development of LVH. Another group was treated for 7 days and then observed for an additional 7 days. This group experienced normalization of Iso-induced cell size, wall thickness, and beta-myosin heavy chain expression. When administered concurrently, PS-519 prevented Iso-induced LVH at 7 days. Furthermore, when PS-519 was given to animals during the second week of continued Iso treatment, these animals also experienced regression of hypertrophy by several measures. The success of proteasome inhibition in preventing LVH development and in promoting LVH regression, even in the face of continued hypertrophic stimulation, demonstrates its potential use as a clinically accessible strategy for treating patients with a variety of LVH-associated cardiomyopathies.