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Changes in circulating miRNA expression in right heart remodeling due to pulmonary hypertension

ABSTRACT: Clinical practice currently faces a significant shortfall in specific biomarkers needed for diagnosing right ventricular (RV) remodeling in patients with pulmonary hypertension (PH). MiRNAs are crucial regulators of cardiovascular development, influencing processes like angiogenesis, cardiomyocyte differentiation, cell cycle, cardiac electrical activity, and cardiomyocyte growth. Furthermore, circulating miRNAs are cell-or tissue-specific, relatively stable in serum, and resistant to degradation factors. These properties make serum miRNAs possible promising biomarkers for predictive diagnosis of cardiovascular disease (CVD). This study systematically screened and identified candidate serum miRNAs as potential diagnostic biomarkers for RV remodeling in PH patients.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE287146 | GEO | 2025/01/18

REPOSITORIES: GEO

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Project description:Rationale: In 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. Objective: To determine the effect of Cfib conditioned media (CM) from the PH calf (PH-CM) on adult rat ventricular myocytes (ARVM) in culture. Methods and Results: Brief 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. Conclusions: These 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.

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Changes in circulating miRNA expression in right heart remodeling due to pulmonary hypertension

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