Abstract P478: Farnesyl Transferase Inhibitor Tipifarnib Reduces Circulating Exosomes And Protects Against Pressure Overload-mediated Cardiac Hypertrophy

Abstract

Clinically, Hypertrophic cardiomyopathy (HCM) in response to pathophysiological stress is one of the major initiating factors for the onset of cardiac remodeling leading to heart failure. Studies have revealed that HCM characterized by left ventricular hypertrophy, hypercontractility, and impaired relaxation is mainly driven by an intricate crosstalk among the multiple cellular and molecular mechanisms, which leads to heart failure. In agreement with this observation, we investigated if the Tipifarnib-mediated reduction/alteration of circulating exosomes mediates cardiac cell communication during HCM. Several studies have shown Tipifarnib as a potential Farnesyl transferase inhibitor. However, in recent past Tipifarnib has been shown to target exosomes biogenesis by several mechanisms such as inhibiting Ras pathway, ESCRT complex etc. Tipifarnib treatment in mice significantly reduced the number of circulating plasma exosomes. We examined the response of Tipifarnib treatment (10 mg/kg body weight) in C57BL6J male mice subjected to transverse aortic constriction (TAC) surgery. Untreated TAC mice had worsening of systolic Left Ventricular function at 4 weeks that further deteriorated at 8 weeks, while the treatment with Tipifarnib substantially improved cardiac functions by reducing cardiac hypertrophy and fibrosis. Exosomes isolated from the serum of sham and TAC mice with or without tipifarnib were used for in vitro cell based analyses. We observed that the exosomes isolated from Tipifarnib treated TAC mice reduced isoproterenol (ISO)-induced cardiomyoblast hypertrophy and fibrosis-associated genes in adult cardiac fibroblasts. Taken together, our studies suggest Tipifarnib protects against pressure overload induced cardiac remodeling and dysfunction by altering hypertrophic and fibrotic gene expression, by potentially reducing circulating exosomes or by altering exosome contents. Ongoing studies will clarify the molecular mechanisms of these observations.