Abstract
Background: No medical therapies exist to treat right ventricular (RV) remodeling and RV failure (RVF), in large part because molecular pathways that are specifically activated in pathologic human RV remodeling remain poorly defined. Murine models have suggested involvement of Wnt signaling, but this has not been well-defined in human RVF.Methods: Using a candidate gene approach, we sought to identify genes specifically expressed in human pathologic RV remodeling by assessing the expression of 28 WNT-related genes in the RVs of three groups: explanted nonfailing donors (NF, n = 29), explanted dilated and ischemic cardiomyopathy, obtained at the time of cardiac transplantation, either with preserved RV function (pRV, n = 78) or with RVF (n = 35).Results: We identified the noncanonical WNT receptor ROR2 as transcriptionally strongly upregulated in RVF compared to pRV and NF (Benjamini-Hochberg adjusted P < 0.05). ROR2 protein expression correlated linearly to mRNA expression (R2 = 0.41, P = 8.1 × 10−18) among all RVs, and to higher right atrial to pulmonary capillary wedge ratio in RVF (R2 = 0.40, P = 3.0 × 10−5). Utilizing Masson's trichrome and ROR2 immunohistochemistry, we identified preferential ROR2 protein expression in fibrotic regions by both cardiomyocytes and noncardiomyocytes. We compared RVF with high and low ROR2 expression, and found that high ROR2 expression was associated with increased expression of the WNT5A/ROR2/Ca2+ responsive protease calpain-μ, cleavage of its target FLNA, and FLNA phosphorylation, another marker of activation downstream of ROR2. ROR2 protein expression as a continuous variable, correlated strongly to expression of calpain-μ (R2 = 0.25), total FLNA (R2 = 0.67), calpain cleaved FLNA (R2 = 0.32) and FLNA phosphorylation (R2 = 0.62, P < 0.05 for all).Conclusion: We demonstrate robust reactivation of a fetal WNT gene program, specifically its noncanonical arm, in human RVF characterized by activation of ROR2/calpain mediated cytoskeleton protein cleavage.
Highlights
Right ventricular failure (RVF) is independently predictive of morbidity and mortality in diverse disease processes including left ventricular failure (LVF), pulmonary hypertension, and congenital heart disease [1,2,3]
We identified the noncanonical WNT receptor ROR2 as transcriptionally strongly upregulated in RVF compared to preserved function (pRV) and NF (Benjamini-Hochberg adjusted P < 0.05)
We identified no clinical confounders between DCMpRV/dilated cardiomyopathy (DCM)-RVF, ICM-pRV/ICM-RVF, and combined pRV/RVF groups (Table 1 and Supplementary Table 2), including no differences in gender, age, ethnicity, body surface area, body
Summary
Right ventricular failure (RVF) is independently predictive of morbidity and mortality in diverse disease processes including left ventricular failure (LVF), pulmonary hypertension, and congenital heart disease [1,2,3]. A recent study illustrated that higher WNT5A serum levels and myocardial expression correlated with worse RV, but not LV, systolic function and with higher likelihood of death or transplant in patients with dilated cardiomyopathy (DCM) [22] Together, these studies have suggested that embryonic or fetal Wnt expression may be reactivated in RV remodeling, akin to the well-established reactivation of fetal programs in LV remodeling. These studies have suggested that embryonic or fetal Wnt expression may be reactivated in RV remodeling, akin to the well-established reactivation of fetal programs in LV remodeling These and other studies demonstrating aberrant WNT signaling in RV remodeling have been limited to transcriptomics in murine models or were narrowly designed in humans such that the potential clinical role of WNT signaling in adaptive and pathologic remodeling, with associated preserved function (pRV) and RVF, respectively, remains incompletely defined [20,21,22,23,24]. Murine models have suggested involvement of Wnt signaling, but this has not been well-defined in human RVF
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