Preprint reports that navitoclax reduced scarring after myocardial infarction in 15-month-old mice
Preprint reports that navitoclax reduced scarring after myocardial infarction in 15-month-old mice
In a preprint dated September 8, the authors tested navitoclax in middle-aged male mice after ischemia-reperfusion: they blocked a coronary artery for one hour, then restored blood flow. They also reanalyzed spatial data from human myocardium after myocardial infarction.
After blood flow is restored, damaged heart muscle heals by forming a scar. Senescent cells accumulate in aging tissue: following stress, they stop dividing and release molecules associated with inflammation and repair. The authors investigated how these cell states affect healing in the aging heart.
Navitoclax blocks some of the proteins that help cells survive. Cells with signs of senescence often depend on these proteins, so the drug is used as a senolytic, a treatment intended to eliminate such cells. In 2019, the drug was given to very old mice before myocardial infarction, and in 2020, it was given to young mice four days after ischemia-reperfusion. The new experiment kept the post-injury treatment schedule and tested it in older animals: navitoclax was given for seven days, starting on the fourth day after ischemia-reperfusion.
After five weeks, the scar occupied 13,61% of the left ventricular area in mice receiving navitoclax and 18,92% in the control group. Heart tissue from treated mice contained more capillaries, fewer immune cells expressing the marker CD45, and fewer nuclei positive for p16 and p21, markers associated with cellular senescence.
The human part of the study addresses a separate question: whether signals associated with senescence are present in myocardium after myocardial infarction. The authors reanalyzed the 2022 human heart atlas using spatial transcriptomics, a method that measures gene activity at spots across a tissue section while preserving their locations within the tissue. Each spot contains several cells. RNA from the gene CDKN2A was detected in 2,2% of spots in the infarct region and 0,11% in control myocardium; the authors interpret this gene as a signal associated with senescence. Regions with a high composite score for senescence-associated genes also had higher scores for gene sets associated with fibrosis and inflammation.