Limits...
The soluble guanylate cyclase activator BAY 58-2667 protects against morbidity and mortality in endotoxic shock by recoupling organ systems.

Vandendriessche B, Rogge E, Goossens V, Vandenabeele P, Stasch JP, Brouckaert P, Cauwels A - PLoS ONE (2013)

Bottom Line: Protection was associated with reduced hypothermia, circulating IL-6 levels, cardiomyocyte apoptosis, and mortality.In contrast to BAY 58-2667, the sGC stimulator BAY 41-2272 and the phosphodiesterase 5 inhibitor Sildenafil did not have any beneficial effect on survival, emphasizing the importance of the selectivity of BAY 58-2667 for diseased vessels and tissues.In conclusion, our results demonstrate the pivotal role of the NO/sGC axis in endotoxic shock.

View Article: PubMed Central - PubMed

Affiliation: Department for Molecular Biomedical Research, VIB, Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.

ABSTRACT
Sepsis and septic shock are associated with high mortality rates and the majority of sepsis patients die due to complications of multiple organ failure (MOF). The cyclic GMP (cGMP) producing enzyme soluble guanylate cyclase (sGC) is crucially involved in the regulation of (micro)vascular homeostasis, cardiac function and, consequently, organ function. However, it can become inactivated when exposed to reactive oxygen species (ROS). The resulting heme-free sGC can be reactivated by the heme- and nitric oxide (NO)-independent sGC activator BAY 58-2667 (Cinaciguat). We report that late (+8 h) post-treatment with BAY 58-2667 in a mouse model can protect against lethal endotoxic shock. Protection was associated with reduced hypothermia, circulating IL-6 levels, cardiomyocyte apoptosis, and mortality. In contrast to BAY 58-2667, the sGC stimulator BAY 41-2272 and the phosphodiesterase 5 inhibitor Sildenafil did not have any beneficial effect on survival, emphasizing the importance of the selectivity of BAY 58-2667 for diseased vessels and tissues. Hemodynamic parameters (blood pressure and heart rate) were decreased, and linear and nonlinear indices of blood pressure variability, reflective for (un)coupling of the communication between the autonomic nervous system and the heart, were improved after late protective treatment with BAY 58-2667. In conclusion, our results demonstrate the pivotal role of the NO/sGC axis in endotoxic shock. Stabilization of sGC function with BAY 58-2667 can prevent mortality when given in the correct treatment window, which probably depends on the dynamics of the heme-free sGC pool, in turn influenced by oxidative stress. We speculate that, considering the central role of sGC signaling in many pathways required for maintenance of (micro)circulatory homeostasis, BAY 58-2667 supports organ function by recoupling inter-organ communication pathways.

Show MeSH

Related in: MedlinePlus

Cardiomyocyte apoptosis.(A) The number of apoptotic cells per heart section were counted and normalized over the total surface area of the tissue section, 2 h post-treatment (n = 3). (B) Representative example of whole heart section for late (+8 h) vehicle control (top-left), and late (+8 h) BAY 58-2667 treatment (bottom-left). Representative example of data processing in BD Attovision software: calculation of total surface area (top-right) and detection of TUNEL events (bottom-right). Data are means ± SEM and comparisons were made between baseline (PBS) and LPS-challenged vehicle control animals (*), and LPS-challenged vehicle control and treatment groups (#) via one-way ANOVA with Fisher's LSD test. ***, p≤0.001; **, p≤0.01 and *, p≤0.05.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3756074&req=5

pone-0072155-g004: Cardiomyocyte apoptosis.(A) The number of apoptotic cells per heart section were counted and normalized over the total surface area of the tissue section, 2 h post-treatment (n = 3). (B) Representative example of whole heart section for late (+8 h) vehicle control (top-left), and late (+8 h) BAY 58-2667 treatment (bottom-left). Representative example of data processing in BD Attovision software: calculation of total surface area (top-right) and detection of TUNEL events (bottom-right). Data are means ± SEM and comparisons were made between baseline (PBS) and LPS-challenged vehicle control animals (*), and LPS-challenged vehicle control and treatment groups (#) via one-way ANOVA with Fisher's LSD test. ***, p≤0.001; **, p≤0.01 and *, p≤0.05.

Mentions: Apoptotic cardiomyocytes were determined by counting the number of TUNEL positive nuclei over the entire surface area of a cross-section of the heart (Fig. 4, A): 2 h after late (+8 h) vehicle treatment, the number of apoptotic cells was increased compared to saline (PBS) and early treatment controls. Late (+8 h) treatment with BAY 58-2667 significantly reduced the amount of apoptotic cells in the heart. However, although not significant, the number of apoptotic cells was also reduced after late BAY 41-2272 treatment, hinting towards the presence of a mixed pool of oxidized- and reduced-heme sGC in the heart, 8 h post-LPS challenge. Cardiac dysfunction is one of the most important determinants of sepsis-induced mortality, both in humans and in animal models [21], [22]. Our results are corroborated by a previous study that showed that sGCα1-deficient mice are sensitized to inflammation-induced cardiac dysfunction, emphasizing the cardioprotective effect of sGCα1-derived cGMP [12]. Although cardiomyocyte apoptosis was reduced thanks to late (+8 h) BAY 58-2667 treatment, this was not reflected in increased cGMP levels in the heart (Fig. 3, B). However, samples were taken 2 h post-treatment, when cGMP levels were still highly increased in the kidney, while this increase could have been more transient in the heart. In addition, very low levels of sGC activation have been shown to elicit full level responses in smooth muscle cells [23], [24], i.e. low level stimulation of sGC and resulting small or even undetectable changes in cGMP levels can have profound cardiovascular effects. Furthermore, reduced cardiomyocyte apoptosis may not only be caused by a direct sGC-mediated effect on the heart, but could also be secondary to a more distal effect on the circulatory system.


The soluble guanylate cyclase activator BAY 58-2667 protects against morbidity and mortality in endotoxic shock by recoupling organ systems.

Vandendriessche B, Rogge E, Goossens V, Vandenabeele P, Stasch JP, Brouckaert P, Cauwels A - PLoS ONE (2013)

Cardiomyocyte apoptosis.(A) The number of apoptotic cells per heart section were counted and normalized over the total surface area of the tissue section, 2 h post-treatment (n = 3). (B) Representative example of whole heart section for late (+8 h) vehicle control (top-left), and late (+8 h) BAY 58-2667 treatment (bottom-left). Representative example of data processing in BD Attovision software: calculation of total surface area (top-right) and detection of TUNEL events (bottom-right). Data are means ± SEM and comparisons were made between baseline (PBS) and LPS-challenged vehicle control animals (*), and LPS-challenged vehicle control and treatment groups (#) via one-way ANOVA with Fisher's LSD test. ***, p≤0.001; **, p≤0.01 and *, p≤0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756074&req=5

pone-0072155-g004: Cardiomyocyte apoptosis.(A) The number of apoptotic cells per heart section were counted and normalized over the total surface area of the tissue section, 2 h post-treatment (n = 3). (B) Representative example of whole heart section for late (+8 h) vehicle control (top-left), and late (+8 h) BAY 58-2667 treatment (bottom-left). Representative example of data processing in BD Attovision software: calculation of total surface area (top-right) and detection of TUNEL events (bottom-right). Data are means ± SEM and comparisons were made between baseline (PBS) and LPS-challenged vehicle control animals (*), and LPS-challenged vehicle control and treatment groups (#) via one-way ANOVA with Fisher's LSD test. ***, p≤0.001; **, p≤0.01 and *, p≤0.05.
Mentions: Apoptotic cardiomyocytes were determined by counting the number of TUNEL positive nuclei over the entire surface area of a cross-section of the heart (Fig. 4, A): 2 h after late (+8 h) vehicle treatment, the number of apoptotic cells was increased compared to saline (PBS) and early treatment controls. Late (+8 h) treatment with BAY 58-2667 significantly reduced the amount of apoptotic cells in the heart. However, although not significant, the number of apoptotic cells was also reduced after late BAY 41-2272 treatment, hinting towards the presence of a mixed pool of oxidized- and reduced-heme sGC in the heart, 8 h post-LPS challenge. Cardiac dysfunction is one of the most important determinants of sepsis-induced mortality, both in humans and in animal models [21], [22]. Our results are corroborated by a previous study that showed that sGCα1-deficient mice are sensitized to inflammation-induced cardiac dysfunction, emphasizing the cardioprotective effect of sGCα1-derived cGMP [12]. Although cardiomyocyte apoptosis was reduced thanks to late (+8 h) BAY 58-2667 treatment, this was not reflected in increased cGMP levels in the heart (Fig. 3, B). However, samples were taken 2 h post-treatment, when cGMP levels were still highly increased in the kidney, while this increase could have been more transient in the heart. In addition, very low levels of sGC activation have been shown to elicit full level responses in smooth muscle cells [23], [24], i.e. low level stimulation of sGC and resulting small or even undetectable changes in cGMP levels can have profound cardiovascular effects. Furthermore, reduced cardiomyocyte apoptosis may not only be caused by a direct sGC-mediated effect on the heart, but could also be secondary to a more distal effect on the circulatory system.

Bottom Line: Protection was associated with reduced hypothermia, circulating IL-6 levels, cardiomyocyte apoptosis, and mortality.In contrast to BAY 58-2667, the sGC stimulator BAY 41-2272 and the phosphodiesterase 5 inhibitor Sildenafil did not have any beneficial effect on survival, emphasizing the importance of the selectivity of BAY 58-2667 for diseased vessels and tissues.In conclusion, our results demonstrate the pivotal role of the NO/sGC axis in endotoxic shock.

View Article: PubMed Central - PubMed

Affiliation: Department for Molecular Biomedical Research, VIB, Ghent, Belgium ; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.

ABSTRACT
Sepsis and septic shock are associated with high mortality rates and the majority of sepsis patients die due to complications of multiple organ failure (MOF). The cyclic GMP (cGMP) producing enzyme soluble guanylate cyclase (sGC) is crucially involved in the regulation of (micro)vascular homeostasis, cardiac function and, consequently, organ function. However, it can become inactivated when exposed to reactive oxygen species (ROS). The resulting heme-free sGC can be reactivated by the heme- and nitric oxide (NO)-independent sGC activator BAY 58-2667 (Cinaciguat). We report that late (+8 h) post-treatment with BAY 58-2667 in a mouse model can protect against lethal endotoxic shock. Protection was associated with reduced hypothermia, circulating IL-6 levels, cardiomyocyte apoptosis, and mortality. In contrast to BAY 58-2667, the sGC stimulator BAY 41-2272 and the phosphodiesterase 5 inhibitor Sildenafil did not have any beneficial effect on survival, emphasizing the importance of the selectivity of BAY 58-2667 for diseased vessels and tissues. Hemodynamic parameters (blood pressure and heart rate) were decreased, and linear and nonlinear indices of blood pressure variability, reflective for (un)coupling of the communication between the autonomic nervous system and the heart, were improved after late protective treatment with BAY 58-2667. In conclusion, our results demonstrate the pivotal role of the NO/sGC axis in endotoxic shock. Stabilization of sGC function with BAY 58-2667 can prevent mortality when given in the correct treatment window, which probably depends on the dynamics of the heme-free sGC pool, in turn influenced by oxidative stress. We speculate that, considering the central role of sGC signaling in many pathways required for maintenance of (micro)circulatory homeostasis, BAY 58-2667 supports organ function by recoupling inter-organ communication pathways.

Show MeSH
Related in: MedlinePlus