Researchers have found that the protein fortilin, which is abundant in the heart, protects it from failure by blocking apoptotic activity. This discovery opens new possibilities in treating age-related heart diseases [1].
When your heart fails you
As menacing at it sounds, heart failure (HF) does not mean that your heart has completely failed, just that it doesn’t pump blood as well as it should anymore. However, HF is still a debilitating and often deadly condition caused by structural and functional impairments of heart muscle.
As with all cardiovascular diseases, HF prevalence has been on the rise. It currently affects 5.7 million Americans and tens of millions more people all over the world. HF is age-related as well [2]: it is the leading cause of hospitalization in people older than 65 and a major cause of mortality.
30-40% of HF patients die within 1 year after the diagnosis and 60-70% within 5 years. This is because HF keeps progressing through pervasive death of cardiomyocytes by apoptosis, even after its upstream causes, such as coronary artery disease and hypertension, have been treated.
Cardiomyocytes (CMs) are the muscle cells of the heart that are responsible for its contraction and relaxation. For decades, the dogma was that CMs stop proliferating soon after birth, similar to what was previously believed about brain cells. Both of those dogmas turned out to be not entirely true: CMs do proliferate in adults, albeit at a very slow rate that does not change the overall picture [3].
Scientists are not entirely sure why CMs stop dividing in humans and many other species, in contrast to some others, such as the zebrafish. If we can find ways to re-ignite proliferation in adult CMs chemically or genetically, this could lead to a breakthrough in treating age-related heart diseases [4]. Until such ways are found, though, we must protect our CMs as well as we can.
Fortilin and p53
Scientists have long been interested in the protective role of fortilin, a protein abundantly expressed in a healthy heart. In people diagnosed with HF, fortilin levels tend to drop sharply. It has been known that fortilin acts as an inhibitor of the p53 protein, and this new paper seeks to elucidate some important aspects of this connection.
P53 is an anti-tumor protein and is sometimes called the guardian of the genome. It acts by detecting specific alterations in the DNA that are characteristic of tumorigenesis and binding to those loci. Then, P53 triggers a cascade of signals that eventually cause the cell to die via apoptosis.
In longevity research, p53 is widely known as a marker of cellular senescence, which illustrates the dual role that senescence plays in the body. Many types of senescent cells strongly express p53 but do not undergo apoptosis (this is what senescence is all about – cells stopping short of apoptotic death). It seems that in patients with HF, p53’s role is more deleterious than beneficial.
Connecting the dots
First, the researchers created genetically engineered mice with fortilin knocked out specifically in the heart. While normal at birth and fertile, those mice started to die as early as 6 weeks since birth and were all dead by 9 weeks. Autopsy showed that their hearts were dilated and thinned, with signs of severe fibrosis and apoptosis in CMs. P53 levels were very high, and the pro-apoptotic genes regulated by p53 were also overexpressed.
Next, these fortilin-KO mice were crossed with p53-KO mice. Full deletion of both p53 and fortilin significantly improved these mice’s lifespan and healthspan and decreased apoptosis in CMs, although not to the level of wild-type mice. The researchers suggest that this is due to fortilin playing an additional protective role by mediating endoplasmic reticulum stress.
Further experiments showed that fortilin affects p53 at least on three levels: it downregulates p53 by suppressing its transcriptional activation; it binds to p53, preventing it from activating pro-apoptotic genes; and, finally, it promotes degradation of p53 by proteasomes, the cellular recyclers of proteins.
The researchers suggest that bumping up fortilin levels in the heart can be a promising avenue in anti-HF therapies. However, we should be careful when downregulating p53, because of its anti-cancer effect. Additionally, since some types of cellular senescence depend heavily on p53, it is possible that fortilin will be tested as a senolytic.
Conclusion
Although the discovered interplay between fortilin and p53 inspires hope, it also highlights the fact that age-related pathologies often spawn from mechanisms that protect us earlier in life. If further research shows that p53 can be downregulated in the heart without sacrificing its anti-tumor activity, this may lead to the development of new therapies against heart failure – at least until we learn to how to make CMs proliferate again.
Literature
[1] Chunhacha, P., Pinkaew, D., Sinthujaroen, P., Bowles, D. E., & Fujise, K. (2021). Fortilin inhibits p53, halts cardiomyocyte apoptosis, and protects the heart against heart failure. Cell Death Discovery, 7(1), 1-10.
[2] Li, H., Hastings, M. H., Rhee, J., Trager, L. E., Roh, J. D., & Rosenzweig, A. (2020). Targeting age-related pathways in heart failure. Circulation research, 126(4), 533-551.
[3] Mollova, M., Bersell, K., Walsh, S., Savla, J., Das, L. T., Park, S. Y., … & Kühn, B. (2013). Cardiomyocyte proliferation contributes to heart growth in young humans. Proceedings of the National Academy of Sciences, 110(4), 1446-1451.
[4] Yutzey, K. E. (2017). Cardiomyocyte proliferation: teaching an old dogma new tricks. Circulation research, 120(4), 627-629.
