Individual cells within the same heart cope differently with high blood pressure, according to a study in human cells and mice by a team of cardiologists and computational biologists. This is the first time researchers have identified distinct differences between heart muscle cells that fail and those that adapt to high blood pressure.
In this new study, cells that adapted to high blood pressure were thicker overall than healthy cells. These thicker cells needed more energy, but could keep the heart beating. Cells that failed to adapt became stretched out and weak, like a worn-out elastic band, and could contract to keep blood pumping.
"These results are the first to show that some cells fail and others adapt to high blood pressure within the same heart. I am very interested in the increased activity of genes that are important for making energy in the cell," said the first author of the research paper.
Authors reconstruct a trajectory of cardiomyocyte remodeling and clarify distinct cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure, by integrating single-cardiomyocyte transcriptome with cell morphology, epigenomic state and heart function. During early hypertrophy, cardiomyocytes activate mitochondrial translation/metabolism genes, whose expression is correlated with cell size and linked to ERK1/2 and NRF1/2 transcriptional networks.
Persistent overload leads to a bifurcation into adaptive and failing cardiomyocytes, and p53 signaling is specifically activated in late hypertrophy. Cardiomyocyte-specific p53 deletion shows that cardiomyocyte remodeling is initiated by p53-independent mitochondrial activation and morphological hypertrophy, followed by p53-dependent mitochondrial inhibition, morphological elongation, and heart failure gene program activation. Human single-cardiomyocyte analysis validates the conservation of the pathogenic transcriptional signatures. Researchers suspect p53 sends cells down a path either of failing or adapting to increased pressure. This gene is familiar to cancer researchers for responding to DNA damage and maintaining cell growth and division.
Ongoing research will continue to investigate the cellular signals that connect p53 to the paths of heart cells failing or adapting to high pressure. Cardiologists of the future may be able to coax cells to adapt to the high pressure of hypertension, a narrow aorta, or heart attack and prevent heart failure.
"Combining computational analysis with experimental medical techniques can extend our knowledge and improve the laboratory bench-to-patients' bedside process of research," said the senior author.
https://www.nature.com/articles/s41467-018-06639-7
Heart cells differently cope with high blood pressure
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