Abstract
Heart transplantation remains the definitive therapy of end-stage heart failure. Ischemia-reperfusion injury occurring during transplantation is a primary determinant of long-term outcome of heart transplantation and primary graft insufficiency. Modification of the nitric oxide/soluble guanylate cyclase/cyclic guanosine monophosphate signaling pathway appears to be one of the most promising among the pharmacological interventional options. We aimed at characterizing the cardio-protective effects of the soluble guanylate cyclase stimulator riociguat in a rat model of heterotopic heart transplantation. Donor Lewis rats were treated orally with either riociguat or placebo for two days (n = 9) in each transplanted group and (n = 7) in donor groups. Following explantation, hearts were heterotopically transplanted. After one hour reperfusion, left ventricular pressure-volume relations and coronary blood flow were recorded. Molecular biological measurements and histological examination were also completed. Left ventricular contractility (systolic pressure: 117 ± 13 vs. 48 ± 5 mmHg, p < 0.001; dP/dtmax: 2963 ± 221 vs. 1653 ± 159 mmHg/s, p < 0.001), active relaxation (dP/dtmin: −2014 ± 305 vs. −1063 ± 177 mmHg/s, p = 0.02; all at 120 µl of left ventricular volume), and alteration of coronary blood flow standardized to heart weight (2.55 ± 0.32 vs. 1.67 ± 0.22 ml/min/g, p = 0.03) were markedly increased following preconditioning with riociguat. Myocardial apoptosis markers were also significantly reduced in the riociguat pretreated group as well as the antioxidant markers were elevated. Pharmacological preconditioning with riociguat decreases ischemia-reperfusion injury and improves donor organ function in our animal model of heart transplantation. Therefore, riociguat might be a potential cardioprotective agent.
Highlights
Heart transplantation remains the definitive therapy of end-stage heart failure
The elevation in tissue cyclic guanosine monophosphate (cGMP) content resulted in a trend (p = 0.16) towards increased phosphorylation ratio of vasodilator-stimulated phosphoprotein in myocardial tissue homogenates of RioHTX hearts (Fig. 1), indicating increased PKG signaling in this group compared with COHTX
Quantitative real-time polymerase chain reaction measurements from myocardial samples showed that mRNA-expression of the master regulator of myocardial energy metabolism and inducer of antioxidant enzymes, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was significantly upregulated in the RioHTX group compared with COHTX (Fig. 2)
Summary
Heart transplantation remains the definitive therapy of end-stage heart failure. Ischemia-reperfusion injury occurring during transplantation is a primary determinant of long-term outcome of heart transplantation and primary graft insufficiency. We aimed at characterizing the cardio-protective effects of the soluble guanylate cyclase stimulator riociguat in a rat model of heterotopic heart transplantation. The deleterious effects of I/R injury are mediated mainly by reactive oxygen (ROS) and nitrogen species (RNS) such as peroxynitrite[2], production of which during ischemia is enhanced This is followed by an extra burst of reactive species generation taking place at reperfusion. Oxidative and nitrosative stress-mediated injury leads to dysfunction of the nitric oxide (NO)/soluble guanylate cyclase (GC-1)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway[4] This pathway www.nature.com/scientificreports has anti-apoptotic and anti-inflammatory effects via regulation of endogenous antioxidant mechanisms, as well as regulation of cell adhesion molecules important in leukocyte invasion, respectively. Our aim was to investigate the cardioprotective capabilities of stimulating the NO/GC-1/cGMP pathway using riociguat in a well-established rodent model of HTX14–16
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