Novel Therapeutic Targets for the Treatment of Right Ventricular Remodeling: Insights from the Pulmonary Artery Banding Model

Figures

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  Figure 1. Advantages and disadvantages of pulmonary artery banding (PAB) model of right ventricular (RV) failure.

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  Figure 2. The pulmonary artery banding (PAB) model of right ventricular (RV) failure recapitulates many features of RV failure observed in pulmonary hypertension (PH) patients. PAB in mice and rats causes RV dilatation and RV wall hypertrophy similar to those observed in PH patients. Many of the pathological characteristics of RV remodeling in PH patients can be seen in the RV of PAB rodents, including increased myocardial inflammation, upregulation of inflammatory mediators, accumulation of extracellular matrix (ECM), myofibroblast differentiation, alterations of epigenetic processes, dysregulation of cardiomyocyte excitation–contraction coupling, oxidative stress, apoptosis of cardiomyocytes and endothelial cells, downregulation of proangiogenic factors, increased glucose uptake and glycolysis, and decreased glucose and fatty acid oxidation.

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  Figure 3. Mechanisms of agents identified to attenuate myocardial fibrosis in pulmonary artery banding (PAB)-induced right ventricular (RV) remodeling. BIBF1000, a nintedanib analogue that targets VEGFRs, PDGFRs, and FGFRs, GSK1904529A, a specific IGF-1R inhibitor, sorafenib, a multi-kinase inhibitor of PDGFRs, VEGFRs, Flt3, c-Kit, c-RAF, and b-RAF, and sunitinib, an inhibitor of PDGFRs, VEGFRs, Flt3, KIT, CSF1R, and RET have been shown to attenuate myocardial fibrosis by inhibiting the activity of cardiac fibroblasts and attenuating the expression of profibrotic genes such as α-SMA (actin alpha 2), fibronectin, collagen, MMPs (matrix metalloproteinases), and TIMPs (tissue inhibitors of metalloproteinases), thus improving RV function in animal models of PAB.

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  Figure 4. Mechanisms of agents improving metabolic alterations in pulmonary artery banding (PAB)-induced right ventricular (RV) remodeling. Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase (PDK), resulting in activation of pyruvate dehydrogenase (PDH), which allows pyruvate to enter the TCA cycle and promote glucose oxidation. While trimetazidine and ranolazine inhibit fatty acid oxidation (FAO), resulting in activation of glucose oxidation, GW0742 activates PPARβ/δ, which mediates the expression of genes regulating metabolic homeostasis. Cumulatively, these agents showed beneficial effects on the RV by improving metabolic changes.

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  Figure 5. Mechanisms of agents attenuating myocardial inflammation and oxidative stress in pulmonary artery banding (PAB)-induced right ventricular (RV) remodeling. E6446, an inhibitor of TLR9, and pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, attenuate inflammatory cell activation and expression of proinflammatory genes. Cromolyn, a mast cell stabilizer, inhibits mast cell degranulation and prevents the release of proinflammatory mediators. MitoQ inhibits mitochondria-derived ROS production and oxidative stress. In summary, these agents inhibit myocardial inflammation and oxidative stress and thereby improve RV function and adaptation to pressure overload.

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  Figure 6. Mechanisms of agents improving epigenetic alterations in pulmonary artery banding (PAB)-induced right ventricular (RV) remodeling. Trichostatin A and valproate target histone deacetylases (HDACs), which remove acetyl groups from lysine residues of histone proteins. RVW208 is an inhibitor of bromodomain-containing protein 4 (BRD4), which is an epigenetic reader that recognizes histone proteins and acts as a transcriptional regulator of various genes. GapmeR, a site-specific antisense oligonucleotide, suppresses the expression of long noncoding RNA H19. All these agents mediate the improvement of RV function and promote its adaptation to pressure overload.

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  Figure 7. Main pathological features of right ventricular (RV) remodeling and main signaling pathways targeted to improve RV adaptation and protection in response to pressure overload. Upon exposure to pressure overload, the RV undergoes changes such as RV wall hypertrophy and dilatation, associated with various pathological processes including myocardial fibrosis, apoptosis of myocardial cells, myocardial inflammation, oxidative stress, metabolic remodeling, and alterations of epigenetic processes. Targeting the signaling pathways driving such changes improves RV function and adaptation to pressure overload.