Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-Nitro-L-Arginine methyl ester-induced hypertension and vascular senescence

Amanda E. Boe, Mesut Eren, Sheila B. Murphy, Christine E. Kamide, Atsuhiko Ichimura, David Terry, Danielle McAnally, Layton H. Smith, Toshio Miyata, Douglas E. Vaughan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

BACKGROUND - : Long-term inhibition of nitric oxide synthase by L-arginine analogues such as N-nitro-L-arginine methyl ester (L-NAME) has been shown to induce senescence in vitro and systemic hypertension and arteriosclerosis in vivo. We previously reported that plasminogen activator inhibitor-1 (PAI-1)-deficient mice (PAI-1) are protected against L-NAME-induced pathologies. In this study, we investigated whether a novel, orally active PAI-1 antagonist (TM5441) has a similar protective effect against L-NAME treatment. Additionally, we studied whether L-NAME can induce vascular senescence in vivo and investigated the role of PAI-1 in this process. METHODS AND RESULTS - : Wild-type mice received either L-NAME or L-NAME and TM5441 for 8 weeks. Systolic blood pressure was measured every 2 weeks. We found that TM5441 attenuated the development of hypertension and cardiac hypertrophy compared with animals that had received L-NAME alone. Additionally, TM5441-treated mice had a 34% reduction in periaortic fibrosis relative to animals on L-NAME alone. Finally, we investigated the development of vascular senescence by measuring p16 expression and telomere length in aortic tissue. We found that L-NAME increased p16 expression levels and decreased telomere length, both of which were prevented with TM5441 cotreatment. CONCLUSIONS - : Pharmacological inhibition of PAI-1 is protective against the development of hypertension, cardiac hypertrophy, and periaortic fibrosis in mice treated with L-NAME. Furthermore, PAI-1 inhibition attenuates the arterial expression of p16 and maintains telomere length. PAI-1 appears to play a pivotal role in vascular senescence, and these findings suggest that PAI-1 antagonists may provide a novel approach in preventing vascular aging and hypertension.

Original languageEnglish (US)
Pages (from-to)2318-2324
Number of pages7
JournalCirculation
Volume128
Issue number21
DOIs
StatePublished - Nov 19 2013

Keywords

  • Aging
  • Hypertension
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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