Sunday, April 02, 2023

Treating a Heart Attack before It Happens

Good news! As they say one ounce of prevention is better than one pound of cure!
Did these scientists find a "cardiac fountain of youth"?

"... researchers ... have now activated a cellular mechanism in healthy mouse hearts that makes these mice resilient to future heart attacks – even when they occur months later. ...
A mouse whose ERBB2 had been activated when it was three months old recovered from cardiac injury that happened five months later. ...
The study ... focused on genetically engineered mice whose cardiomyocytes – the cells that make up the heart muscle tissue – overexpress a gene that triggers cell division in mice and other mammals, including humans. In previous studies ... had found that the gene, ERBB2, causes cell division in cardiomyocytes – a remarkable occurrence because at around the time of birth these cells lose their capacity to multiply. ...
When, in previous studies, ... team had managed to trigger the division of cardiomyocytes – by switching on ERBB2 briefly in these cells – overall heart function actually decreased temporarily, rather than improving straightaway. This happened because the ERBB2-expressing cardiomyocytes underwent dedifferentiation, meaning that they reverted to a less specialized state, closer to that of a fetal heart. This, in turn, limited their ability to contract, which is needed for proper heart function. But once the overexpression had stopped, the cardiomyocytes underwent redifferentiation – that is, they became highly specialized again – and cardiac performance improved.
In the new study, ... notice some significant differences in gene expression between the two populations. ... “We had assumed that everything returns to normal after ERBB2 is switched off in the cardiomyocytes. Yet here we were, seeing a different genetic pattern – overexpression in some genes and underexpression in others – following ERBB2 activation. In other words, we found long-term effects. ...
To test this hypothesis, the researchers reversed the order of their previous experiments with ERBB2. Instead of switching ERBB2 on in injured mice to make their cardiomyocytes divide, they first switched it on in healthy mice for a few weeks and then switched it off again. Next, the researchers observed how the hearts of those mice coped with an injury. The result: Mice that had been made to overexpress ERBB2 recovered, but others did not. “The data made our jaws drop,” ... “We had found a cardiac fountain of youth in those mice, a novel way of making the heart younger and stronger.””
This discovery made ... wonder whether ERBB2 expression could be calibrated for improved cardiac performance. “It made us think that ERBB2 wasn’t just a switch that prevents differentiation, but part of a mechanism that could make the heart younger and more resilient,” ..."

From the abstract:
"Cardiomyocyte proliferation and dedifferentiation have fueled the field of regenerative cardiology in recent years, whereas the reverse process of redifferentiation remains largely unexplored. Redifferentiation is characterized by the restoration of function lost during dedifferentiation. Previously, we showed that ERBB2-mediated heart regeneration has these two distinct phases: transient dedifferentiation and redifferentiation. Here we survey the temporal transcriptomic and proteomic landscape of dedifferentiation–redifferentiation in adult mouse hearts and reveal that well-characterized dedifferentiation features largely return to normal, although elements of residual dedifferentiation remain, even after the contractile function is restored. These hearts appear rejuvenated and show robust resistance to ischemic injury, even 5 months after redifferentiation initiation. Cardiomyocyte redifferentiation is driven by negative feedback signaling and requires LATS1/2 Hippo pathway activity. Our data reveal the importance of cardiomyocyte redifferentiation in functional restoration during regeneration but also protection against future insult, in what could lead to a potential prophylactic treatment against ischemic heart disease for at-risk patients."

Treating a Heart Attack before It Happens - Life Sciences | Weizmann Wonder Wander - News, Features and Discoveries A preventive procedure, performed on healthy mice, improved their recovery from later-occurring cardiac injury, reshaping our knowledge of regeneration in hearts – and possibly other organs



Mouse hearts after injury. Scar tissue (red) represents the extent of damage to the heart muscle. The damage was significantly reduced in mice whose ERBB2 gene had been temporarily activated (bottom row), compared to the controls (upper row)


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