Objective:
Enhanced expression of PAI-1 (plasminogen activator inhibitor-1) has been implicated in atherosclerosis formation in humans with obesity and metabolic syndrome. However, little is known about the effects of pharmacological targeting of PAI-1 on atherogenesis. This study examined the effects of pharmacological PAI-1 inhibition on atherosclerosis formation in a murine model of obesity and metabolic syndrome.
Approach and Results:
LDL receptor-deficient (
ldlr
−/−
) mice were fed a Western diet high in cholesterol, fat, and sucrose to induce obesity, metabolic dysfunction, and atherosclerosis. Western diet triggered significant upregulation of PAI-1 expression compared with normal diet controls. Addition of a pharmacological PAI-1 inhibitor (either PAI-039 or MDI-2268) to Western diet significantly inhibited obesity and atherosclerosis formation for up to 24 weeks without attenuating food consumption. Pharmacological PAI-1 inhibition significantly decreased macrophage accumulation and cell senescence in atherosclerotic plaques. Recombinant PAI-1 stimulated smooth muscle cell senescence, whereas a PAI-1 mutant defective in LRP1 (LDL receptor-related protein 1) binding did not. The prosenescent effect of PAI-1 was blocked by PAI-039 and R2629, a specific anti-LRP1 antibody. PAI-039 significantly decreased visceral adipose tissue inflammation, hyperglycemia, and hepatic triglyceride content without altering plasma lipid profiles.
Conclusions:
Pharmacological targeting of PAI-1 inhibits atherosclerosis in mice with obesity and metabolic syndrome, while inhibiting macrophage accumulation and cell senescence in atherosclerotic plaques, as well as obesity-associated metabolic dysfunction. PAI-1 induces senescence of smooth muscle cells in an LRP1-dependent manner. These results help to define the role of PAI-1 in atherosclerosis formation and suggest a new plasma-lipid-independent strategy for inhibiting atherogenesis.
Within a matter of 48 hours, the promotion of the article entitled "Prevalence of unprofessional social media content among young vascular surgeons," aptly demonstrated the power of social media and the dangers of unconscious bias as it spread across Twitter with the #MedBikini tag. In response, vascular surgeons from around the world have come together in a call to action to address the article and highlight the misogynistic, racist, and oppressive issues facing young surgeons today. We, as female vascular surgery trainees, would like to make our own call to action. The publication of this article (now appropriately retracted) has encouraged important dialogue among female vascular surgeons, male colleagues who support #HeforShe initiatives, other disadvantaged and marginalized groups in surgery, and the future generation of surgeons who will pave the path forward. We have converged to discuss the current climate of our specialty and have determined that now is an opportunity for change.It is essential that we pursue ethics, as well as excellence, in surgical practice and research. The inherent conscious and unconscious biases, poor study design, and unethical data collection methods within the article have demonstrated a critical flaw within the editorial process of the Journal of Vascular Surgery (JVS). We are disappointed to find ourselves represented by the article. The publication was both tone deaf toward, and discriminatory against, us as professionals, trainees, and women. As vascular surgeons, we must hold ourselves to a higher standard. Our call to action for the JVS includes the following:1. Re-examine the review process for publication of ethical abstracts from regional and national meetings and manuscripts, and provide training in ethical research for all editors and reviewers.
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