Proteasome inhibition promotes regression of left ventricular hypertrophy

Abstract

Background: Left ventricular hypertrophy (LVH) is a quiet epidemic in our society. Over 20 million people have LVH secondary to hypertension, valvular heart disease, and ischemic cardiomyopathies. Unfortunately, 15-20% of patients treated medically (ACE-inhibitors) or surgically (aortic valve replacement for aortic stenosis) will continue to have LVH. This group maintains a significantly higher risk of cardiovascular events compared to those with reduced or normal left ventricular mass. Nuclear factor kappa B (NFkB) is a ubiquitous transcription factor central to the injury response. Activation of NFkB is dependent upon degradation of its inhibitory protein by the proteosome. Experiments in transgenic mice have demonstrated an important role for NFkB in the development of LVH. The purpose of the current project is to evaluate a clinically accessible proteosome inhibitor on the development of murine LVH. We hypothesized that NFkB inhibition would prevent the development of LVH and promote its regression. Methods: We utilized a murine model of reversible hypertrophy by administering isoproterenol (ISO - 100 mg/kg) intraperitoneally for 7-14 days. Proteosome inhibitors have been tested in human trials of stroke, solid tumors, and multiple myeloma. We delivered the proteosome inhibitor, PS-519 (PS - 1mg/kg), both concurrently and after ISO treatment. LVH was quantified by three Methods: heart weight/body weight ratios, measurement of histologic sections, and transthoracic echocardiography (TTE). Groups were compared by analysis of variance with Bonferonni-Dunn post-hoc analysis set with 95% confidence intervals. Results: Seven days after receiving ISO, mice developed significant LVH as measured by heart weight ratios, histology, and TTE compared to control and vehicle animals. After withdrawal of ISO, animals were observed for an additional 7 days when it was observed that all 3 markers of LVH had resolved to the level of control. When administered concurrently, PS-519 prevented ISO-induced LVH at 7 days. As an additional step, ISO was given for 7 days in order to develop LVH and continued for an additional 7 days. PS-519 was then given from day 8-14 in order to determine its effect on mice with existing hypertrophy. The below graph depicts TTE data for left ventricular posterior wall thickness during diastole. PS-519 caused regression of the previously developed ISO-induced LVH (*ISO delivered for 14 days versus ISO for 14 days with PS-519 days 8-14, p<0.001). Conclusion: Isoproterenol administration and withdrawal reproducibly results in the development and subsequent regression of LVH. Not only did PS-519 inhibit the development of LVH, but it also promoted regression. These results demonstrate a potential role for proteosome inhibition as a novel and clinically accessible strategy for treating patients with a variety of LVH-associated cardiomyopathies.