Inhibition of aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide

Abstract

Pathological remodeling of the myocardium has long been known to involve oxidant signaling, but strategies using systemic antioxidants have generally failed to prevent it. We sought to identify key regulators of oxidant-mediated cardiac hypertrophy amenable to targeted pharmacological therapy. Specific isoforms of the aquaporin water channels have been implicated in oxidant sensing, but their role in heart muscle is unknown. RNA sequencing from human cardiac myocytes revealed that the archetypal AQP1 is a major isoform. AQP1 expression correlates with the severity of hypertrophic remodeling in patients with aortic stenosis. The AQP1 channel was detected at the plasma membrane of human and mouse cardiac myocytes from hypertrophic hearts, where it colocalized with NADPH oxidase-2 and caveolin-3. We show that hydrogen peroxide (H2O2), produced extracellularly, is necessary for the hypertrophic response of isolated cardiac myocytes and that AQP1 facilitates the transmembrane transport of H2O2 through its water pore, resulting in activation of oxidant-sensitive kinases in cardiac myocytes. Structural analysis of the amino acid residues lining the water pore of AQP1 supports its permeation by H2O2. Deletion of Aqp1 or selective blockade of the AQP1 intrasubunit pore inhibited H2O2 transport in mouse and human cells and rescued the myocyte hypertrophy in human induced pluripotent stem cell–derived engineered heart muscle. Treatment of mice with a clinically approved AQP1 inhibitor, Bacopaside, attenuated cardiac hypertrophy. We conclude that cardiac hypertrophy is mediated by the transmembrane transport of H2O2 by the water channel AQP1 and that inhibitors of AQP1 represent new possibilities for treating hypertrophic cardiomyopathies.

High Na+ Salt Diet and Remodeling of Vascular Smooth Muscle and Endothelial Cells

“…This increase in oxidative stress was attributed to inflammation, as well as to renal epithelial cell damage, by activation of NADPH oxidase [ 136 , 138 , 140 , 142 ] NOX2/NOX4-derived ROS [ 138 , 142 ]. Such an increase in oxidative stress was reported to activate nuclear factor-kappa B [ 141 ], as well as several mechanisms implicated in cell membrane ionic transporters, in addition to aquaporin 1 sensitive transmembrane transporter of hydrogen peroxide [ 136 , 143 , 144 ] and osmolyte sensor ( Figure 3 ). However, recent literature in the field showed that high -salt-sensitive hypertension is due, at least in part, to damage of the glycocalyx of both vascular endothelial [ 136 ] and vascular smooth muscle [ 20 ] cells.…”

Targeting Aquaporins in Novel Therapies for Male and Female Breast and Reproductive Cancers

“…Bacopasides I and II extracted from the Indian medicinal herb water hyssop (Bacopa monnieri) differentially inhibited AQP1-mediated water and ion fluxes and reduced motility, invasiveness, and lamellipodial formation of HT29 colon cells [72,180]. Inhibition of AQP1 intrasubunit pores by Bacopaside II impaired stress-induced H 2 O 2 influx, protecting against hypertrophic heart disease in mouse and human cardiac models [54]. A Chinese herbal medicinal extract, compound Kushing injection, reduced growth and invasiveness of colon cancer, breast cancer, and glioblastoma cell lines and altered the expression of genes including AQPs [188]; however, specific actions on AQP functions remain to be defined.…”

“…The full spectra of solutes permeable through AQP channels remain to be defined. In addition to water, AQP1 allows transport of CO 2 [52], H 2 O 2 [53,54], NO [55], and NH 3 [56]. Several classes of mammalian AQPs function as ion channels.…”

Cardiac Fibrosis and Fibroblasts

“…The inhibition of H 2 O 2 translocation, by the aquaporin 1 inhibitor bacopaside, resulted in the suppression of hypertrophic responses and fibrotic responses in vitro. The treatment of mice with a clinically approved extract containing bacopasides attenuated cardiac hypertrophy and fibrosis [ 92 ]. These results suggest that aquaporin is a promising target for the treatment of cardiac fibrosis as well as hypertrophy.…”