Abstract 299: Pulmonary Hypertension Activates Cardiac Fibroblasts To Release Paracrine Factors Regulating Cardiac Myocyte Dedifferentiation
In virtually all models of heart failure, prognosis is ultimately determined by right ventricular (RV) function. Thus understanding the unique cellular mechanisms that contribute to RV dysfunction is of critical importance. We have approached this question by studying a large animal model that has significant resonance with human disease: exposure of the neonatal calf to hypobaric hypoxia. This model demonstrates rapid onset of severe pulmonary hypertension (PH) and significant RV dysfunction. Strikingly, the RV of these animals shows a chamber-specific increase in markers of inflammation and local infiltration of activated pro-remodeling macrophages that are proportionate to the rise in PA pressure. In order to test the hypothesis that this inflammatory milieu directly contributes to myocyte dysfunction, we examined the effects of conditioned media (CM) from cardiac fibroblasts isolated from the PH calf on normal adult rat ventricular myocytes (ARVM) in culture. Even brief exposure (<2 days) to RV-CM results in rapid and marked dedifferentiation of ARVM to a neonatal-like phenotype that exhibits spontaneous contractile behavior. Dedifferentiated cells maintain viability for over 30 days with continued expression of cardiomyocyte proteins including TnI, sarcomeric actinin, and desmin. This response is not seen in ARVM exposed to CM from fibroblasts collected from the hypoxic LV or from the normoxic RV. We have characterized the factor(s) that are present in the RV-CM and have established that the active components are proteins with a mol wt >30 kDa and that inflammatory cytokines such as IL-18 are necessary but not sufficient to effect this phenotypic change. These data suggest that local and perhaps focal inflammation in the RV, induced by the combination of pressure overload and hypoxia, has the capacity to signal a phenotypic transformation in a population of RV cardiocytes, which likely contributes to chamber specific dysfunction. Therapies that target and interrupt this inflammatory process either by preventing in-migration of inflammatory cells or by blocking cell-cell signaling have the potential to prevent RV dysfunction.
Author Disclosures: L.A. Walker: None R.D. Brown: None K.R. Stenmark: None P.M. Buttrick: None.
- © 2014 by American Heart Association, Inc.