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Inhibition of Ras-GTPase Farnesylation and the Ubiquitin-Proteasome System or Treatment with Angiotensin-(1-7) Attenuates Spinal Cord Injury-Induced Cardiac Dysfunction
- Publication Year :
- 2011
-
Abstract
- Cardiovascular diseases are one of the principal causes of death and disability in people with spinal cord injury (SCI). The present study was designed to investigate if acute treatment with FPTIII (an inhibitor of Ras-GTPase farnesylation) or MG132 (an inhibitor of ubiquitin-proteasome pathway [ UPS]) or administration of angiotensin( 1-7), also known as Ang-(1-7), (a known inhibitor of cardiac NF-kB) would be cardioprotective. The weight drop technique produced a consistent contusive injury of the spinal cord at the T13 segment. Hearts were isolated from rats either 6 months (SCI-6) or 12 months (SCI-12) after SCI. Hearts were perfused for 30 min and then subjected to 30 min ischemia followed by 30 min reperfusion (I/R). Recovery of cardiac function after I/R was measured as left ventricular developed pressure (P-max) and coronary flow (CF). Drugs were given during perfusion before hearts were exposed to ischemia and reperfusion. Percent recovery (%R) in P-max and CF in hearts from control animals were 48 +/- 6 and 50 +/- 5, respectively, whereas none of the hearts from animals with SCI recovered after 30 min of ischemia. Treatment with FPTIII, MG 132, or Ang-(1-7) before ischemia for 30min led to significant recovery of heart function following ischemia in SCI-6 but not in SCI-12 animals. Thus we have shown that acute treatments with FPTIII, MG132, or Ang-(1-7) improve cardiac recovery following ischemic insult in animals with SCI and may represent novel therapeutic agents for preventing ischemia-induced cardiac dysfunction in patients with SCI.<br />Cardiovascular diseases are one of the principal causes of death and disability in people with spinal cord injury (SCI). The present study was designed to investigate if acute treatment with FPTIII (an inhibitor of Ras-GTPase farnesylation) or MG132 (an inhibitor of ubiquitin-proteasome pathway [UPS]) or administration of angiotensin-(1-7), also known as Ang-(1-7), (a known inhibitor of cardiac NF-kB) would be cardioprotective. The weight drop technique produced a consistent contusive injury of the spinal cord at the T13 segment. Hearts were isolated from rats either 6 months (SCI-6) or 12 months (SCI-12) after SCI. Hearts were perfused for 30 min and then subjected to 30 min ischemia followed by 30 min reperfusion (I/R). Recovery of cardiac function after I/R was measured as left ventricular developed pressure (P(max)) and coronary flow (CF). Drugs were given during perfusion before hearts were exposed to ischemia and reperfusion. Percent recovery (%R) in P(max) and CF in hearts from control animals were 48±6 and 50±5, respectively, whereas none of the hearts from animals with SCI recovered after 30 min of ischemia. Treatment with FPTIII, MG 132, or Ang-(1-7) before ischemia for 30 min led to significant recovery of heart function following ischemia in SCI-6 but not in SCI-12 animals. Thus we have shown that acute treatments with FPTIII, MG132, or Ang-(1-7) improve cardiac recovery following ischemic insult in animals with SCI and may represent novel therapeutic agents for preventing ischemia-induced cardiac dysfunction in patients with SCI.
- Subjects :
- Cardiac function curve
Proteasome Endopeptidase Complex
Ischemia
Protein Prenylation
Pharmacology
Rats, Sprague-Dawley
chemistry.chemical_compound
Renin–angiotensin system
MG132
medicine
Animals
Spinal cord injury
Spinal Cord Injuries
business.industry
Ubiquitin
Spinal cord
medicine.disease
Peptide Fragments
Rats
Disease Models, Animal
medicine.anatomical_structure
Proteasome
chemistry
Cardiovascular Diseases
Anesthesia
ras Proteins
Neurology (clinical)
Angiotensin I
business
Perfusion
Proteasome Inhibitors
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....eab3d3744b04d261081751c06aa8d1d0