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Inhibition of matrix metalloproteinase activity in vivo protects against vascular hyporeactivity in endotoxemia
Jonathan J Cena1, Manoj M Lalu, Woo Jung Cho
1Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
Abstract:
Persistent arterial hypotension is a hallmark of sepsis and is believed to be caused, at least in part, by excess nitric oxide (NO). NO can combine with superoxide to produce peroxynitrite, which activates matrix metalloproteinases (MMPs). Whether MMP inhibition in vivo protects against vascular hyporeactivity induced by endotoxemia is unknown. Male Sprague-Dawley rats were administered either bacterial lipopolysaccharide (LPS, 4 mg/kg ip) or vehicle (pyrogen-free water). Later (30 min), animals received the MMP inhibitor doxycycline (4 mg/kg ip) or vehicle (pyrogen-free water). After LPS injection (6 h), animals were killed, and aortas were excised. Aortic rings were mounted in organ baths, and contractile responses to phenylephrine or KCl were measured. Aortas and plasma were examined for MMP activity by gelatin zymography. Aortic MMP and inducible nitric oxide synthase (iNOS) were examined by immunoblot and/or immunohistochemistry. Doxycycline prevented the LPS-induced development of ex vivo vascular hyporeactivity to phenylephrine and KCl. iNOS protein was significantly upregulated in aortic homogenates from endotoxemic rats; doxycycline did not alter its level. MMP-9 activity was undetectable in aortic homogenates from LPS-treated rats but significantly upregulated in the plasma; this was attenuated by doxycycline. Plasma MMP-2 activities were unchanged by LPS. Specific MMP-2 activity was increased in aortas from LPS-treated rats. This study demonstrates the in vivo protective effect of the MMP inhibitor doxycycline against the development of vascular hyporeactivity in endotoxemic rats.
Insights
Matrix metalloproteinase (MMP) inhibition protects against sepsis-induced vascular hyporeactivity. Doxycycline, an MMP inhibitor, prevented endotoxemia-induced changes in rat aortic function, demonstrating its protective effects in vivo.
Area of Science:
- Sepsis and Cardiovascular Pathophysiology
- Pharmacology and Therapeutics
- Biochemistry and Molecular Biology
Background:
- Persistent arterial hypotension is a key feature of sepsis, potentially driven by excess nitric oxide (NO).
- Nitric oxide (NO) can react with superoxide to form peroxynitrite, activating matrix metalloproteinases (MMPs).
- The protective role of MMP inhibition against endotoxemia-induced vascular hyporeactivity in vivo remains unclear.
Purpose of the Study:
- To investigate whether matrix metalloproteinase (MMP) inhibition in vivo protects against vascular hyporeactivity induced by endotoxemia.
- To evaluate the effect of doxycycline, an MMP inhibitor, on vascular function and MMP activity in an endotoxemia model.
Main Methods:
- Male Sprague-Dawley rats were administered lipopolysaccharide (LPS) to induce endotoxemia.
- Animals received either the MMP inhibitor doxycycline or vehicle.
- Vascular contractile responses of aortic rings were measured ex vivo.
- MMP activity in aortas and plasma was assessed using gelatin zymography.
Main Results:
- Doxycycline administration prevented the development of vascular hyporeactivity to phenylephrine and KCl in LPS-treated rats.
- Inducible nitric oxide synthase (iNOS) protein levels were upregulated in endotoxemic rat aortas, unaffected by doxycycline.
- MMP-9 activity was significantly upregulated in plasma and attenuated by doxycycline, while aortic MMP-2 activity increased.
Conclusions:
- Matrix metalloproteinase (MMP) inhibition demonstrates a protective effect against vascular hyporeactivity in endotoxemic rats.
- Doxycycline's protective mechanism may involve modulating MMP activity rather than affecting iNOS levels.
- This study highlights the potential therapeutic role of MMP inhibitors in managing sepsis-induced vascular dysfunction.
