Commonly used cardiovascular agents, including the angiotensin-converting enzyme (ACE) inhibitor enalapril and the beta blocker carvedilol, are also top candidates found in our analysis. The induction of fibrosis by the renin–angiotensin system is evident in multiple organ systems, including the eye, and the release of profibrotic cytokines and growth factors is common in the pathogenesis of both PVR and renal fibrosis.
56 Similar to how TGF-β induces the epithelial-to-mesenchymal transition (EMT) of RPE cells into contractile myofibroblasts in PVR, TGF-β induces EMT of renal tubular epithelial cells in renal fibrosis.
57,58 However, despite inhibition of TBF-β expression and fibrosis in the kidney with systemic ACE inhibitors, a similar dosage with ACE inhibitors in a primary human study did not significantly decrease the levels of cytokines and growth factors such as TGF-β, VEGF, IL-6, or PDGF in the aqueous humor of patients with RD or affect the incidence of PVR development.
59 Nonetheless, it is unclear if the systemic intake and accumulation of ACE inhibitors in the eye have a direct effect, and the pursuit of a more direct ocular delivery route remains an attractive option for future experiments. Similar to ACE inhibitors, beta blockers (especially carvedilol and metoprolol) also suppress renin secretion and angiotensin II formation.
60 Additionally, carvedilol is widely used clinically for chronic heart failure and following myocardial infarction in part due to its significant suppression of myocardial fibrosis and cardiac remodeling, and this effect is further enhanced when carvedilol is used in combination with enalapril, as shown in the CARMEN trial.
61 Although the antifibrotic activity of carvedilol is not well understand, it has shown antifibrotic activity in the liver of rats by overexpressing both microRNA-200a, which modulates EMT markers, and SMAD7, which attenuates TBF-β and other inflammatory markers.
62 Both classes of cardiovascular agents require additional preclinical and clinical trials to further assess their antifibrotic effects in the eye and to fine-tune the dosing and delivery.