Enzyme Block Shields Mouse Hearts From Scarring After Attack

One of the most feared consequences of a heart attack is not the attack itself but what follows it. In the weeks after the damaged muscle begins to heal, the heart often becomes stiffened by an overgrowth of scar tissue, a process known as fibrosis, which progressively undermines its ability to pump blood. Now a team of researchers in Japan reports that blocking a single enzyme, BCAT1, can dramatically reduce this scarring in mice and preserve cardiac function, even when treatment is delayed until well after the injury has occurred. The findings, published in the Journal of Clinical Investigation, point to a new way of thinking about how fibrotic disease takes hold and how it might be stopped.

The work was led by Professor Michio Nakaya of the Research Institute of Environmental Medicine at Nagoya University, in collaboration with colleagues from Kyushu University and Tokushima University. Their central discovery concerns the metabolic machinery that scar-forming cells rely on to manufacture collagen, the structural protein that makes up roughly a fifth of the raw material in the form of a single amino acid: proline. By disrupting the supply chain for this building block, the team found they could throttle collagen production at its source.

Fibrosis is not unique to the heart. The same runaway deposition of collagen-based scar tissue can afflict the liver, where chronic injury can progress to cirrhosis, and it is estimated to contribute to as many as 45 percent of deaths in developed countries. Despite this enormous disease burden, no definitive therapy exists that directly suppresses the fibrotic process itself. Current treatments generally manage symptoms or slow progression rather than halting the underlying cellular program that turns healthy tissue into stiff, nonfunctional scar.

To understand why the heart is so vulnerable, it helps to look at the cells responsible. After inflammation or injury, specialized cells called myofibroblasts flood into the damaged area and begin producing collagen on an industrial scale, reinforcing the wound much as rebar reinforces concrete. In the short term this is protective, preventing the weakened heart wall from rupturing under pressure. But when the response becomes chronic, the accumulating collagen stiffens the myocardium, impairs contraction, and sets the stage for heart failure, which frequently develops in patients in the months and years following a myocardial infarction.

Because approximately 20 percent of collagen consists of proline, the Nagoya-led team reasoned that the way myofibroblasts produce and supply this amino acid might be a critical vulnerability. They began by comparing genes activated by physical stress with those switched on in mouse hearts after a heart attack, searching for molecular players common to both settings. This screen identified five overlapping candidates, among them Bcat1, the gene encoding branched-chain amino acid transaminase 1. The researchers homed in on BCAT1 because its role in myofibroblasts had never been explored, leaving open the possibility that it represented an untapped therapeutic target.

What they found was striking. In healthy mouse hearts, BCAT1 was barely detectable. But after a heart attack, levels of the enzyme rose sharply in collagen-producing cells, climbing in step with the progression of fibrosis. Follow-up experiments revealed that BCAT1 activates a cellular pathway that maintains the supply of proline, effectively functioning as part of the material-delivery system that fibrotic cells use to sustain their enormous output of collagen. In other words, the enzyme does not merely accompany scarring; it helps feed it.

The causal role of BCAT1 became clear when the team studied mice genetically engineered to lack the enzyme. After suffering a heart attack, these animals produced fewer proline-related enzymes and less collagen than their normal counterparts. They developed less scar tissue and, crucially, maintained better heart function than control mice. The histological evidence was equally compelling: heart tissue sections stained with Picrosirius red, which highlights collagen in red, showed markedly reduced collagen deposition in BCAT1-deficient mice 28 days after a heart attack compared with normal mice subjected to the same injury.

Genetic deletion, however, is not a practical treatment for patients who arrive at the hospital after an attack has already happened. So the researchers turned to pharmacology, testing a BCAT1 inhibitor called ERG240 in mice following induced heart attacks. The results were notable for their timing flexibility: ERG240 administration reduced scarring and preserved heart function even when treatment began seven days after injury, during the transition from the acute inflammatory phase to the chronic fibrotic phase. This delayed-treatment window matters enormously in clinical terms, because real-world interventions almost always occur after a heart attack rather than before it. A therapy that only works prophylactically would be of limited use; one that can reverse course after fibrosis has begun is far more valuable.

The mouse findings also appear to translate to human disease. When the team analyzed human heart tissue from patients with heart failure, they found elevated BCAT1 levels linked to increased fibrosis, suggesting that a similar enzyme-driven mechanism operates in human hearts. Intriguingly, the researchers also detected higher BCAT1 levels in the livers of patients with fatty liver disease, hinting that the same proline-supply pathway may drive fibrosis in organs well beyond the heart. The team’s next step is to determine whether the BCAT1-proline pathway also promotes fibrosis in the liver and other tissues, and to develop clinically applicable BCAT1-targeted therapies while assessing their safety, optimal dosing, and efficacy.

Perhaps the most attractive feature of BCAT1 as a drug target is its selectivity. Because the enzyme is mostly absent from healthy tissue and becomes primarily active in scar-forming cells, blocking it should, in principle, suppress pathological collagen production without disturbing the normal collagen turnover that healthy organs depend on. That specificity could translate into fewer side effects than existing anti-fibrotic treatments, which often act on broader pathways and carry a heavier burden of toxicity. As Nakaya put it, “We found that BCAT1 is a new driver of excessive collagen production in the fibrotic heart by increasing the supply of proline, a major building block of collagen. Importantly, pharmacological inhibition of BCAT1 suppressed cardiac fibrosis and preserved cardiac function, even when treatment started after fibrosis had begun to develop.” If the pathway holds up in further studies across organs and eventually in human trials, a metabolic vulnerability shared by fibrotic diseases of the heart, liver, and beyond may finally have a common weak point.

Subject of Research: The role of the enzyme BCAT1 in proline-dependent collagen production and cardiac fibrosis after heart attack

Article Title: Blocking enzyme reduces heart failure risk after heart attack in mice

Article References: Blocking enzyme reduces heart failure risk after heart attack in mice. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: BCAT1, cardiac fibrosis, heart attack, heart failure, collagen, proline, myofibroblasts, ERG240, Nagoya University, Journal of Clinical Investigation, enzyme inhibitor, fatty liver disease