Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-nitro-L-arginine methyl ester-induced hypertension and vascular senescence.

Abstract

BACKGROUND:

Long-term inhibition of nitric oxide synthase by L-arginine analogues such as N(ω)-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(Ink4a) expression and telomere length in aortic tissue. We found that L-NAME increased p16(Ink4a) 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(Ink4a) 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.

• Authors: 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
• Journal: Circulation (Circulation) Vol. 128 Issue 21 Pg. 2318-24 (Nov 19 2013) ISSN: 1524-4539 [Electronic] United States
• PMID: 24092817 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 5-chloro-2-(((2-(4-(diphenylmethyl)piperazin-1-yl)-2-oxoethoxy)acetyl)amino)benzoate
• Enzyme Inhibitors
• Piperazines
• Serpin E2
• Serpine2 protein, mouse
• para-Aminobenzoates
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Aorta (cytology, drug effects)
• Blood Pressure (drug effects)
• Cardiomegaly (chemically induced, drug therapy)
• Cellular Senescence (drug effects)
• Drug Interactions
• Enzyme Inhibitors (pharmacology)
• Female
• Hypertension (chemically induced, drug therapy)
• Male
• Mice
• Mice, Inbred C57BL
• NG-Nitroarginine Methyl Ester (pharmacology)
• Piperazines (chemistry)
• Rats
• Rats, Wistar
• Serpin E2 (antagonists & inhibitors)
• Structure-Activity Relationship
• Telomere (drug effects)
• para-Aminobenzoates (chemistry)