Abstract
AimsHeart failure is often preceded by cardiac hypertrophy, which is characterized by increased cell size, altered protein abundance, and actin cytoskeletal reorganization. Profilin is a well-conserved, ubiquitously expressed, multifunctional actin-binding protein, and its role in cardiomyocytes is largely unknown. Given its involvement in vascular hypertrophy, we aimed to test the hypothesis that profilin-1 is a key mediator of cardiomyocyte-specific hypertrophic remodelling.Methods and resultsProfilin-1 was elevated in multiple mouse models of hypertrophy, and a cardiomyocyte-specific increase of profilin in Drosophila resulted in significantly larger heart tube dimensions. Moreover, adenovirus-mediated overexpression of profilin-1 in neonatal rat ventricular myocytes (NRVMs) induced a hypertrophic response, measured by increased myocyte size and gene expression. Profilin-1 silencing suppressed the response in NRVMs stimulated with phenylephrine or endothelin-1. Mechanistically, we found that profilin-1 regulates hypertrophy, in part, through activation of the ERK1/2 signalling cascade. Confocal microscopy showed that profilin localized to the Z-line of Drosophila myofibrils under normal conditions and accumulated near the M-line when overexpressed. Elevated profilin levels resulted in elongated sarcomeres, myofibrillar disorganization, and sarcomeric disarray, which correlated with impaired muscle function.ConclusionOur results identify novel roles for profilin as an important mediator of cardiomyocyte hypertrophy. We show that overexpression of profilin is sufficient to induce cardiomyocyte hypertrophy and sarcomeric remodelling, and silencing of profilin attenuates the hypertrophic response.
Highlights
Heart failure (HF), a leading cause of morbidity and mortality, is often preceded by cardiac hypertrophy, a process in which cardiomyocytes exhibit increased size, changes in protein abundance, and cytoskeletal and sarcomeric reorganization.[1]
To determine whether profilin-1 abundance in the heart is altered in different animal models of cardiac hypertrophy and HF, western blot analysis was performed on ventricular tissues from mice that underwent transverse aortic constriction (TAC) (Figure 1A and see Supplementary material online, Figure S1A)[35] and from Gaq-overexpressing mice and appropriate controls (Figure 1B and see Supplementary material online, Figure S1A).[25]
Neonatal rat ventricular myocytes (NRVMs) were isolated to assess cardiomyocyte-specific expression levels of Pfn[1] in cells treated with PE or ET1 to stimulate hypertrophy
Summary
Heart failure (HF), a leading cause of morbidity and mortality, is often preceded by cardiac hypertrophy, a process in which cardiomyocytes exhibit increased size, changes in protein abundance, and cytoskeletal and sarcomeric reorganization.[1]. Multifunctional, and highly conserved actin-binding proteins of 15 kDa.[2,3] Four profilin genes have been identified in mammals, Pfn1– Pfn[4,4] while the gene family in invertebrates is often less complex. In Drosophila, for example, a single profilin isoform is encoded by chickadee.[5] Profilins are found in different cellular locations where they perform diverse cytoplasmic and nuclear roles.[4] Pfn[1] encodes profilin-1, the isoform found in vertebrate cardiac tissue.[6] It promotes actin polymerization by catalyzing ADP to ATP exchange on G-actin[3,7] and through transient interactions of the profilin– ATP –actin complex with the fast-growing ‘barbed’ end of F-actin.[8] Profilin associates with many ligands via its poly-L-proline-binding domain, linking it to proteins involved with actin polymerization, and to Rac and Rho effector molecules, nuclear export receptors,
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