Cardiovascular disease commonly leads to heart failure, characterized by fibrosis, a type of tissue scarring. Initially, cardiac fibrosis works to repair damaged heart tissue, but it can become excessive and harmful. Exploring the mechanisms behind fibrosis is a major focus in cardiovascular research, and scientists have now identified a crucial genetic mechanism driving this process — along with pinpointing a target for reversing it.
Cardiovascular disease often leads to heart failure, characterized by fibrosis, a type of tissue scarring. Initially, cardiac fibrosis works to repair damaged heart tissue, but it can become excessive and harmful. Zeroing in on the mechanisms behind fibrosis is a major focus in cardiovascular research. Scientists at the Lewis Katz School of Medicine at Temple University have uncovered a vital genetic mechanism driving this process and identified a novel target for potentially reversing it.
“In pathological fibrosis, resident fibroblasts in the heart that are activated by tissue injury transform into myofibroblasts that produce and secrete excess extracellular matrix,” explained John W. Elrod, PhD, the Director of the Aging + Cardiovascular Discovery Center (ACDC) and a Cardiovascular Sciences Professor at the Katz School of Medicine, who is a senior investigator on this new study. “The activation of fibroblasts often relies on transforming growth factor-β (TGFβ), and for the first time, we show that TGFβ boosts the enzyme ATP-citrate lyase (ACLY), which then localizes in the cell nucleus and interacts at specific gene sites, driving and maintaining fibrosis through epigenetic means.”
The team led by Dr. Elrod found that inhibiting ACLY hinders myofibroblast formation and the activation of epigenetic sites. This discovery positions ACLY as an innovative therapeutic target for reversing fibrosis. Their findings were detailed in a paper published online in the journal Nature Cardiovascular Research.
This new research builds upon prior work from Dr. Elrod’s lab, particularly a previous discovery of a signaling pathway that stimulates myofibroblast formation through histone demethylation. Histone demethylation is an epigenetic alteration involved in gene transcription and similar processes that regulate genetic information flow in cells. Earlier studies from the team also showcased that blocking a metabolic pathway called glutaminolysis could reverse myofibroblast-driven fibrosis in an epigenetic-dependent manner.
ACLY plays a central role in the current research by Dr. Elrod and his team, due to its connection with glutaminolysis, metabolite levels, and acetyl-CoA production. ACLY is also crucial for sustaining histone acetylation, which impacts processes determining cell fate. In this study, Dr. Elrod’s team, led by MD/PhD student Michael P. Lazaropoulos, delved deeper into the involvement of ACLY and specifically, the role of histone acetylation in governing myofibroblast fate.
In initial experiments conducted in cardiac fibroblasts isolated from mice, the researchers showed that ACLY is essential for myofibroblast differentiation and that blocking it reverses the pro-fibrotic nature of myofibroblasts, transitioning the cells to a less harmful state. Using a new genetic system that enabled simultaneous gene deletion and protein tracking, they demonstrated that ACLY moves to the cell nucleus, where it interacts with a transcription factor called SMAD. With the assistance of SMAD, ACLY is guided to specific locations in the genome, where its involvement in histone acetylation promotes fibrosis.
“Our research indicates that ACLY binding to SMAD enables ACLY to concentrate at specific genetic sites, setting in motion genetic programming that supports myofibroblast formation and a fibrotic nature,” explained Dr. Elrod.
Further, Dr. Elrod’s team illustrated that blocking ACLY can reverse myofibroblast fate, prompting the cells to revert to a non-diseased state. This was showcased in mouse cardiac fibroblasts as well as in cardiac fibroblasts obtained from heart failure patients. ACLY inhibition was carried out experimentally in two ways, through a pharmacological intervention and a genetic disruption.
“Based on our observations, we can confidently assert that acetylation-based epigenetic mechanisms are crucial in sustaining the fibrotic process in heart cells,” Dr. Elrod highlighted. “Moreover, we now have a target — ACLY — for potentially reversing fibrosis, as shown in our studies involving animal and human patient cells.”
Dr. Elrod anticipates advancing the translational impact of these new findings by exploring pharmacological agents capable of inhibiting ACLY. “One of the agents tested in our experiments has been under investigation in clinical trials for other applications,” he noted. Alongside investigating therapeutic approaches, his team aims to extend their findings to other conditions featuring pathological fibrosis.