Abstract
Circulating extracellular vesicles, including exosomes, and their content have been implicated in cardiac tissue remodeling during cardiovascular disease progression. However, their role in cardiac hypertrophy and heart failure is very limited. Therefore, we investigated the role of circulating exosomes in cardiac dysfunction and remodeling in a transverse aortic constriction (TAC) model of heart failure using a recently identified exosome biogenesis inhibitor, Tipifarnib. Ten-week-old C57BL6J male mice were randomized into three groups i.e., Sham, TAC and Tipifarnib treated (10 mg/kg) TAC (TAC-Tip). The untreated TAC mice showed a significant increase in circulating exosomes along with gradual development of cardiac hypertrophy accompanied with reduced cardiac functions and increased fibrosis. On the contrary, TAC-Tip mice showed a significant reduction in circulating exosomes and remarkably improved cardiac left ventricular functions, reduced cardiac hypertrophy, fibrosis, and systemic inflammation. Strikingly, when primary mouse cardiac fibroblast cells were treated with exosomes derived from serum of TAC mice, the fibrosis related genes expression was significantly amplified compared to those treated with exosomes from TAC-Tip mice serum. Further, systemic injections of TAC-serum exosomes in normal, uninjured mice for 8 weeks, reduced cardiac function and increased cardiomyocyte hypertrophy. Small RNA sequencing analysis of serum exosomes from TAC and TAC-Tip mice displayed an extensively differential exosomal miRNAs profile. To evaluate the crucial role of miRNA in the circulating exosomes, we selected miR 331-5p based on the most differentially expressed miR and validated its expression in heart tissue and serum exosomes of Sham, TAC and TAC-Tip mice. Functional studies showed miR 331-5p inhibited HOXC8, a critical regulator of fibrosis. Overall, our studies reveal a mechanism by which treatment of Tipifarnib in TAC mice, alters not just the exosome numbers but also circulating exosomes content including miR 331-5p that directly inhibits HOXC8 and reduces fibrosis. Thus, Tipifarnib mediated inhibition of circulating exosomes may serve as a viable strategy to prevent progressive cardiac remodeling to heart failure.
Published Version
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