Abstract
RationaleIn virtually all models of heart failure, prognosis is determined by right ventricular (RV) function; thus, understanding the cellular mechanisms contributing to RV dysfunction is critical. Whole organ remodeling is associated with cell-specific changes, including cardiomyocyte dedifferentiation and activation of cardiac fibroblasts (Cfib) which in turn is linked to disorganization of cytoskeletal proteins and loss of sarcomeric structures. However, how these cellular changes contribute to RV function remains unknown. We’ve previously shown significant organ-level RV dysfunction in a large animal model of pulmonary hypertension (PH) which was not mirrored by reduced function of isolated cardiomyocytes. We hypothesized that factors produced by the endogenous Cfib contribute to global RV dysfunction by generating a heterogeneous cellular environment populated by dedifferentiated cells.ObjectiveTo determine the effect of Cfib conditioned media (CM) from the PH calf (PH-CM) on adult rat ventricular myocytes (ARVM) in culture.Methods and resultsBrief exposure (<2 days) to PH-CM results in rapid, marked dedifferentiation of ARVM to a neonatal-like phenotype exhibiting spontaneous contractile behavior. Dedifferentiated cells maintain viability for over 30 days with continued expression of cardiomyocyte proteins including TnI and α-actinin yet exhibit myofibroblast characteristics including expression of α-smooth muscle actin. Using a bioinformatics approach to identify factor(s) that contribute to dedifferentiation, we found activation of the PH Cfib results in a unique transcriptome correlating with factors both in the secretome and with activated pathways in the dedifferentiated myocyte. Further, we identified upregulation of periostin in the Cfib and CM, and demonstrate that periostin is sufficient to drive cardiomyocyte dedifferentiation.ConclusionsThese data suggest that paracrine factor(s) released by Cfib from the PH calf signal a phenotypic transformation in a population of cardiomyocytes that likely contributes to RV dysfunction. Therapies targeting this process, such as inhibition of periostin, have the potential to prevent RV dysfunction.
Highlights
In a number of animal models, inflammation contributes to the progression of left ventricular heart failure (HF) and in patients with left ventricular (LV) failure, the severity of HF correlates with plasma levels of inflammatory cytokines [1, 2]
We identified upregulation of periostin in the cardiac fibroblasts (Cfib) and conditioned media (CM), and demonstrate that periostin is sufficient to drive cardiomyocyte dedifferentiation. These data suggest that paracrine factor(s) released by Cfib from the pulmonary hypertension (PH) calf signal a phenotypic transformation in a population of cardiomyocytes that likely contributes to right ventricular (RV)
Prognosis in virtually all models of heart failure is determined by right ventricular (RV) function [8, 9], there is a relative paucity of biologic information about the cellular mechanisms that contribute to RV dysfunction
Summary
In a number of animal models, inflammation contributes to the progression of left ventricular heart failure (HF) and in patients with left ventricular (LV) failure, the severity of HF correlates with plasma levels of inflammatory cytokines [1, 2]. The HH model demonstrates significant resonance with human disease, and in particular, displays progressive deterioration of RV function [12] As such it provides a nice context within which to study biologic factors that drive progressive RV dysfunction. Remodeling is often accompanied by changes in cardiomyocyte expression of sarcomeric and cytoskeletal proteins, resulting in a cellular phenotype resembling the embryonic or neonatal state, with re-expression of the fetal gene program and isoform switching of multiple sarcomeric proteins [16] These dedifferentiated myocytes, defined in part by their loss of sarcomeric structure and fetal gene expression, have been found in infarction border zones [17], the volume overloaded myocardium, and fibrillating atria [18]. While postulated to be initially protective against cardiac stress, continued activation of cardiomyocyte dedifferentiation is likely maladaptive [19]
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