Researchers at Fudan University in Shanghai demonstrated that delivering the Pcsk5 gene via an AAV vector, combined with the GLP-1 drug semaglutide, improves cardiac function and blood vessel growth in mice after heart attacks. The Nature Communications study offers new insights into heart biology…
A combination of gene therapy and the GLP-1 drug semaglutide has been shown to restore cardiac function in mice following heart attacks, according to researchers at Fudan University in Shanghai, China. The study, published in Nature Communications, proposes a targeted viral gene therapy carrying the Pcsk5 gene as a strategy to stimulate blood vessel growth and muscle repair in damaged heart tissue. The work builds on earlier research into the use of peptides in recovery after myocardial infarction and unveils new insights into heart biology.
Recovering from a heart attack is extremely difficult. The event typically leads to muscle scarring and permanent loss of cardiac function. Individuals who have experienced a heart attack face increased risks of heart failure, kidney failure, and stroke. The need to address these patients is made urgent by the fact that cardiovascular disease remains the number one killer worldwide.
The team at Fudan University, led by Jieyu Guo, focused on a gene called PCSK5. PCSK5 is part of a broader family of proteins that includes its more famous cousin, PCSK9, which has long been associated with cholesterol and heart health. Research had also implicated PCSK5 in heart development and cholesterol levels. However, until this paper, it was unclear how much PCSK5 influences heart attack recovery or how it helps boost heart function.
Guo and her colleagues first examined data from myocardial infarction patients to understand real-world PCSK5 expression levels. They found that PCSK5 levels are elevated in patients who have had a heart attack, suggesting a role for the protein in heart recovery. More strikingly, increased PCSK5 levels six months after the cardiac event correlated with improved cardiac function. This led the researchers to consider the therapeutic benefit of delivering PCSK5 directly to the heart following a heart attack.
The team tested the idea in animal models of myocardial infarction. They used an adeno-associated virus serotype 9 AAV9 to deliver the mouse Pcsk5 gene or a negative control to cardiac tissue in a population of male mice aged 6 to 8 weeks. In mice receiving AAV-Pcsk5, the researchers observed improved systolic function and smaller infarctions when measuring 28 days after injury, compared with the control group. If this effect translates to human studies, Guo and her co-authors speculate that patients could benefit from receiving a dose of Pcsk5 after a heart attack.
The next step was to determine how Pcsk5 improves heart health on a mechanistic level. The researchers harvested cells from the myocardial infarction mice and measured total gene expression levels. They saw that a significant number of angiogenesis blood vessel formation genes, such as VEGFA vascular endothelial growth factor A , were increased in cells from the AAV-Pcsk5 mice versus the AAV-control group. This suggested that Pcsk5 might boost VEGFA’s ability to stimulate vascular growth in heart tissue.
That was precisely what the team observed when they examined capillary and arteriole growth in the mice themselves. They saw that mice treated with AAV-Pcsk5 exhibited increased blood vessel density over their control counterparts. The team also looked at Pcsk5 knockout mice and similarly noted a reduction in blood vessels compared to wild-type mice. If overexpressing this gene could help bring blood to affected areas in mice, the team reasoned, this could be a rejuvenating opportunity for patients around the world.
Amid their mechanistic investigations, Guo and her colleagues found that Pcsk5 can be activated by the well-known ERK signaling pathway. ERK is a key pathway in 40% of cancers and involves a cascade of proteins, including RAS and MAPK. This raised a question: could GLP-1 drugs, which can also trigger ERK signaling, be used to enhance Pcsk5 even further? The idea builds on past research suggesting that GLP-1s could play an important role in helping reduce heart attack mortality.
The team decided to see if they could improve blood vessel formation by delivering semaglutide, the glucagon-like peptide-1 GLP-1 known commercially as Wegovy or Ozempic, as a complementary treatment to PCSK5. They first tested the idea in human epithelial cells in vitro and saw an increase in both PCSK5 expression and in genes associated with angiogenesis. In mouse heart attack models, the team found that semaglutide encouraged capillary and arteriole growth. Further investigations showed that the presence of semaglutide helped reduce infarct size and improve systolic function compared with mice that did not receive the peptide.
When Guo and her colleagues noted that these beneficial effects were lost in Pcsk5 knockout mice, they concluded that Pcsk5 could be at least one mechanism by which GLP-1s impact heart health. The research provides new insights into heart biology and points to a growing role for both gene therapy and GLP-1s in cardiac health. The authors also suggest that delivering the gene therapy alongside semaglutide further enhanced Pcsk5 expression and its downstream effects.
The authors acknowledge their study has significant limitations. For example, the team worked with an all-male population of mice due to higher baseline VEGFA levels in female mice. Since cardiovascular disease is the number one cause of death for women, this presents a significant gap in the study. They also recognize that it will be important to study the effects of PCSK5 expression over longer periods in future work.
There is also a major gap between mouse and human studies. What works in animal models often does not prove effective in clinical trials. There are major outstanding questions about an AAV-based approach to treating disease, particularly AAV9, considering how this vector has led to patient deaths through acute lung, liver, and heart failure. Another significant caveat is the lack of insight into which type of myocardial infarction PCSK5 is best suited to treat. The most dangerous form of heart attack, known as an ST-segment elevation myocardial infarction, is a bridge the team will have to cross when approaching human trials.
Despite these caveats, the authors conclude by saying that they believe PCSK5 is “a promising therapeutic target for cardiovascular ischemic diseases.” The authors did not disclose any plans for clinical trials at this stage, and Guo and her team did not respond to requests for comment. Millions of people worldwide would certainly benefit from any drug that improves post-heart attack outcomes. Given that in countries like the United States, someone has a heart attack every 40 seconds, time is ticking.
Millie Hoe contributed to this article.
Peptides referenced: Semaglutide, Glucagon, GLP-1.
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