Inhibition of Ras-GTPase Farnesylation and the Ubiquitin-Proteasome System or Treatment with Angiotensin-(1–7) Attenuates Spinal Cord Injury-Induced Cardiac Dysfunction

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 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.

Cardioprotective effects of phosphocreatine on myocardial cell ultrastructure and calcium-sensing receptor expression in the acute period following high level spinal cord injury

“…Varying degrees of myocardial injury and necrosis have been reported following SCI and these mechanisms are generally controversial and poorly characterized (5). Since cardiovascular failure and dysfunction remain leading causes of mortality and disability in patients with SCI, numerous potentially cardioprotective compounds have been recently investigated in animal models, including FPTIII, MG132 or Ang-(1-7) (14). Unfortunately, the majority of successful treatments require immediate administration, generally directly following the initial SCI assault or within the first 6 h. Preliminary studies in the last two decades have indicated that post-SCI administration of PCr, however, is able to effectively improve functional heart contractile recovery, lower diastolic pressure and mediate abnormal myocardial enzyme release relatively late in the acute SCI period (15).…”

The effect of Iridoids effective fraction of Valeriana jatamansi Jones on movement function in rats after acute cord injury and the related mechanism

“…Rats were deeply anesthetized with pentobarbital sodium (50 mg/kg) and perfused transcardially as previously described [17], Briefly, the chest of rats was opened and aortic cannulation was carried out using normal saline via the left ventricle of the rat until liquid became clear. Following this, 4% paraformaldehyde in PBS (300 ml) was used for continuous perfusion, and the perfusion was stopped when the liver was white and the limbs and trunk were stiff.…”

Angiotensin-(1–7) Receptor Mas Deficiency Does Not Exacerbate Cardiac Atrophy Following High-Level Spinal Cord Injury in Mice

“…The recently discovered non-canonical axis of the RAS including angiotensin-(1-7) which acts via the G protein-coupled receptor (GPCR) Mas exert mostly opposite functions to the classical RAS (Bader et al, 2018) and the Ang-(1-7)-Mas axis has been shown to play a key role in the maintenance of the structure and function of the heart (Santos et al, 2006). For example, an acute treatment with Ang-(1-7) before ischemia/reperfusion injury led to significant recovery of heart function following ischemia in hearts isolated from spinal cord injured rats (Benter et al, 2011). The main actions of Ang-(1-7) in the heart are regulation of genes involved in fibrosis in cardiac fibroblasts via Mas, NOreleasing, antioxidative, NO-increasing, direct anti-hypertrophic effects on cardiomyocytes and regulation of endothelial function (Santos et al, 2006;Rabelo et al, 2008;Bader, 2013).…”