A new target and a potential cure of cardiac hypertrophy inspired from plant biology

Cardiovascular disease remains the world’s number one killer and advanced heart failure is a major contributor. In the process leading to the disease, the heart muscle undergoes a enlargement called hypertrophy that hampers its contractile and relaxation properties. It has long been known that oxidative stress is a trigger of hypertrophy but exactly how oxidants trigger it is unknown, and many clinical studies have shown that systemic anti-oxidants are ineffective.

Hydrogen peroxide: double-edged

The team of Jean-Luc Balligand, WELBIO investigator and president of the Institute of Experimental and Clinical Research, identified the key role of hydrogen peroxide. Produced in low concentrations by many cell types, including heart cells, it can exert beneficial effects. At higher concentrations under stress, however, hydrogen peroxide initiates a cascade of adverse signalling which, among other things, results in hypertrophy.

A solution in the plant world?

However, they found that the membrane-bound NADPH oxidase activated under stress produced hydrogen peroxide in the extracellular space. Although hydrogen peroxide can slowly diffuse back into the cell, this is not very efficient nor compatible with specific signaling in subcellular compartments. By analogy with some plant aquaporins that can transport both water and hydrogen peroxide across membranes, they screened the transcriptome of human and rodent cardiac myocytes and found that the archetypal aquaporin-1 is strongly expressed and upregulated in the heart of patients with cardiac hypertrophy.

The team then analyzed the molecular structure of the water pore of aquaporin-1 and used several experimental approaches to show that aquaporin-1 facilitates the passage of hydrogen peroxide (which makes it a bona fide ‘peroxiporin’) and regulates the development of hypertrophy in rodents and in human cardiac cells.

In search of a drug that would block aquaporin-1 and interrupt oxidant signaling, the team again found an answer in the plant world. An extract of Brahmi, a plant used for centuries in traditional Ayurvedic medicine, contains a molecule, bacopaside, which specifically blocks water transport by aquaporin-1. The team showed that it also efficiently blocks the passage of hydrogen peroxide into cardiac cells and prevents the development of hypertrophy.

‘Repurposing’ the remedy for cardiovascular indications

The researchers were able to confirm that a standardised extract of Brahmi added to rodent food protects them against cardiac hypertrophy in response to hemodynamic stress such as high blood pressure. Brahmi is easily accessible and has already been used in clinical studies for neurological diseases, without showing any notable toxicity. It could now be ‘repurposed’ for cardiovascular indications in patients at risk of developing hypertrophy that leads to heart failure. A pilot study, just launched, will test this hypothesis.

These encouraging results pave the way for the development of more potent molecules to block aquaporin and, hopefully, treat heart failure more efficiently.

Source: Institut de Recherche Expérimentale et Clinique (IREC, UCLouvain)
Illustration : Par Forest & Kim Starr, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=6109556

Reference : Montiel, V., Bella, R., Michel, L. Y. M., Esfahani, H., De Mulder, D., Robinson, E. L., … Balligand, J.-L. (2020). Inhibition of aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide. Science Translational Medicine, 12(564), eaay2176. https://doi.org/10.1126/scitranslmed.aay2176