Targeting Cardiovascular Aging to Reduce Disease Risk - News Center

"Northwestern Medicine scientists have uncovered new insights into how a protein called PAI-1 contributes to cardiovascular aging and how inhibiting it may help mitigate cardiovascular disease, according to recent findings published in The Journal of Clinical Investigation. "We found very consistent results that by lowering PAI-1 expression, we can prevent aging-like changes in the arterial vasculature or by giving a drug that block PAI-1, we can even reverse vascular aging in mice," said Douglas Vaughan, MD, the Irving S. Cutter Professor of Medicine Emeritus and senior author of the study."

"The plasminogen activator inhibitor-1 (PAI-1) protein, which circulates in the blood, is encoded by the SERPINE1 gene and is a known contributor to cardiovascular aging and age-related cardiovascular disease. Previous work led by Vaughan discovered that members of an extended Amish family in Indiana who carried a mutation in the SERPINE1 gene that led to lower levels of PAI-1 and who were protected against multiple aspects of biological aging and cardiometabolic dysfunction."

"The investigators used CRISPR-Cas9 gene editing to breed mice with the SERPINE1 mutation and then compared their cardiovascular responses to control mice without the mutation. They found that mice with the SERPINE1 mutation demonstrated a 20 percent longer survival than mice without the mutation, and when exposed to vascular stress, the mutant mice demonstrated lower systolic hypertension and preserved diastolic function in the heart's left ventricular compared to controls. Mice without the SERPINE1 mutation, however, demonstrated signs of accelerated cardiovascular aging in response to vascular stress."

PAI-1, encoded by SERPINE1, contributes to cardiovascular aging and age-related disease. Lowering PAI-1 expression or pharmacologic blockade prevents and can reverse vascular aging in mice. A SERPINE1 mutation identified in an extended Amish family reduces PAI-1 levels and associates with protection against biological aging and cardiometabolic dysfunction. CRISPR-Cas9–engineered mice carrying the SERPINE1 mutation lived about 20% longer and showed attenuated systolic hypertension and preserved left ventricular diastolic function under vascular stress compared with controls. Control mice exhibited accelerated cardiovascular aging with stress. Single-cell transcriptomics were employed to analyze aortic cell-level changes in mutant mice.

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