Soluble guanylate cyclase (sGC) stimulator vericiguat alleviates myocardial ischemia-reperfusion injury by improving microcirculation

Cai, Yun; Zhang, Beijian; Shalamu, Adilan; Gao, Tingwen; Ge, Junbo

doi:10.21037/atm-22-2583

Cited by 9 publications

(9 citation statements)

References 42 publications

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“…After the baseline experiments, vericiguat at a dose of 5 μmol/L was administrated to evaluate the effects of acute vericiguat therapy. As reported by Cai et al [ 11 ], vericiguat at a dose of 1 to 10 μmol/L is considered safe and capable of promoting an increase in cGMP in cardiomyocytes. The same pacing protocols for electrophysiological study and optical mapping were repeated 20 minutes after the start of vericiguat perfusion.…”

Section: Methodsmentioning

confidence: 87%

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Vericiguat suppresses ventricular tachyarrhythmias inducibility in a rabbit myocardial infarction model

Chang,

Lee,

et al. 2024

PLoS ONE

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Background The VICTORIA trial demonstrated a significant decrease in cardiovascular events through vericiguat therapy. This study aimed to assess the potential mechanisms responsible for the reduction of cardiovascular events with vericiguat therapy in a rabbit model of myocardial infarction (MI). Methods A chronic MI rabbit model was created through coronary artery ligation. Following 4 weeks, the hearts were harvested and Langendorff perfused. Subsequently, electrophysiological examinations and dual voltage-calcium optical mapping studies were conducted at baseline and after administration of vericiguat at a dose of 5 μmol/L. Results Acute vericiguat therapy demonstrated a significant reduction in premature ventricular beat burden and effectively suppressed ventricular arrhythmic inducibility. The electrophysiological influences of vericiguat therapy included an increased ventricular effective refractory period, prolonged action potential duration, and accelerated intracellular calcium (Cai) homeostasis, leading to the suppression of action potential and Cai alternans. The pacing-induced ventricular arrhythmias exhibited a reentrant pattern, attributed to fixed or functional conduction block in the peri-infarct zone. Vericiguat therapy effectively mitigated the formation of cardiac alternans as well as the development of reentrant impulses, providing additional anti-arrhythmic benefits. Conclusions In the MI rabbit model, vericiguat therapy demonstrates anti-ventricular arrhythmia effects. The vericiguat therapy reduces ventricular ectopic beats, inhibiting the initiation of ventricular arrhythmias. Furthermore, the therapy successfully suppresses cardiac alternans, preventing conduction block and, consequently, the formation of reentry circuits.

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Section: Methodsmentioning

confidence: 87%

“…According to a previous study [ 12 ], the EC 50 of vericiguat for sGC activation is 1.005 ± 0.145 mmol/L. Vericiguat at a dose of 1 to 10 μmol/L is considered safe and capable of promoting an increase in cGMP in cardiomyocytes [ 11 ]. Therefore, we chose a larger dose to ensure the pharmacological effects in the animal model.…”

Section: Discussionmentioning

confidence: 99%

Vericiguat suppresses ventricular tachyarrhythmias inducibility in a rabbit myocardial infarction model

Chang,

Lee,

et al. 2024

PLoS ONE

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“…As a stimulator of sGC, vericiguat can not only stimulate sGC directly but also cooperate with NO, resulting in the increase of cGMP ( Kang and Lamb, 2022 ). Previous studies have shown that vericiguat of 3 mg/kg can significantly increase the content of cGMP in mice ( Cai et al, 2022 ). Our results show compared with the control group, the content of cGMP was decreased in the DOX group ( p < 0.05).…”

Section: Resultsmentioning

confidence: 98%

“…Mice in the vericiguat-treated group received a gavage of vericiguat (MCE HY-16774) for two weeks prior to injection of DOX and continued until 72 h after the DOX injection. The dosage of vericiguat was set to 3 mg/kg/day, as used previously in other studies ( Follmann et al, 2017 ; Cai et al, 2022 ). Mice were monitored daily and then euthanized 72 h post-injection.…”

Section: Methodsmentioning

confidence: 99%

Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy

Han

et al. 2023

Front. Pharmacol.

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Background: The chemotherapeutic doxorubicin (DOX) promotes severe skeletal muscle atrophy, which induces skeletal muscle weakness and fatigue. Soluble guanylate cyclase (sGC) contributes to a variety of pathophysiological processes, but whether it is involved in DOX-induced skeletal muscle atrophy is unclear. The present study aimed to stimulate sGC by vericiguat, a new oral sGC stimulator, to test its role in this process.Methods: Mice were randomly divided into four groups: control group, vericiguat group, DOX group, and DOX + vericiguat group. Exercise capacity was evaluated before the mice were sacrificed. Skeletal muscle atrophy was assessed by histopathological and molecular biological methods. Protein synthesis and degradation were monitored in mice and C2C12 cells.Results: In this study, a significant decrease in exercise capacity and cross-sectional area (CSA) of skeletal muscle fibers was found in mice following DOX treatment. Furthermore, DOX decreased sGC activity in mice and C2C12 cells, and a positive correlation was found between sGC activity and CSA of skeletal muscle fibers in skeletal muscle. DOX treatment also impaired protein synthesis, shown by puromycin detection, and activated ubiquitin-proteasome pathway. Following sGC stimulation, the CSA of muscle fibers was elevated, and exercise capacity was enhanced. Stimulation of sGC also increased protein synthesis and decreased ubiquitin-proteasome pathway. In terms of the underlying mechanisms, AKT/mTOR and FoxO1 pathways were impaired following DOX treatment, and stimulation of sGC restored the blunted pathways.Conclusion: These results unravel sGC stimulation can improve skeletal muscle atrophy and increase the exercise capacity of mice in response to DOX treatment by enhancing protein synthesis and inhibiting protein degradation. Stimulation of sGC may be a potential treatment of DOX-induced skeletal muscle dysfunction.

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“…40 Research has shown that VIT can protect against oxidative stress-induced damage in neurons, reduce the risk of heart attack and stroke, and alleviate symptoms of inflammatory diseases such as rheumatoid arthritis and Crohn's disease. 41,42 SIRT1, an NAD+-dependent deacetylase, has been shown to protect cells from oxidative stress by regulating the expression of genes involved in antioxidant defense, inflammation, and cell survival. 43 In addition to its role in antioxidant defense, SIRT1 also plays a role in the regulation of cell metabolism, which can also be affected by oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Favorable osteogenic activity of vericiguat doped in β-tricalcium phosphate: In vitro and in vivo studies

Tao,

Shen

2024

J Biomater Appl

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Recently, more and more studies have shown that guanylate cyclase, an enzyme that synthesizes cyclic guanosine monophosphate (cGMP), plays an important role in bone metabolism. Vericiguat (VIT), a novel oral soluble guanylate cyclase stimulator, directly generates cyclic guanosine monophosphate and reduce the death incidence from cardio-vascular causes or hospitalization. Recent studies have shown beneficial effects of VIT in animal models of osteoporosis, but very little is currently known about the effects of VIT on bone defects in the osteoporotic states. Therefore, in this study, β-tricalcium phosphate (β-TCP) was used as a carrier to explore the effect of local VIT administration on the repair of femoral metaphyseal bone defects in ovariectomized (OVX) rats. When MC3T3-E1 was cultured in the presence of H2H2, VIT, similar to Melatonin (MT), therapy could increase the matrix mineralization and ALP, SOD2, SIRT1, and OPG expression, reduce ROS and Mito SOX production, RANKL expression, Promote the recovery of mitochondrial membrane potential. In the OVX rat model, VIT increases the osteogenic effect of β-TCP and better results were obtained at a dose of 5 mg. Local use of VIT can inhibit increased OC, BMP2 and RUNX2 expressions in bone tissue, while decreased SOST and TRAP expressions by RT-PCR and immunohistochemistry. Thereby, VIT stimulates bone regeneration and is a promising candidate for promoting bone repair in osteoporosis.

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Soluble guanylate cyclase (sGC) stimulator vericiguat alleviates myocardial ischemia-reperfusion injury by improving microcirculation

Cited by 9 publications

References 42 publications

Vericiguat suppresses ventricular tachyarrhythmias inducibility in a rabbit myocardial infarction model

Vericiguat suppresses ventricular tachyarrhythmias inducibility in a rabbit myocardial infarction model

Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy

Favorable osteogenic activity of vericiguat doped in β-tricalcium phosphate: In vitro and in vivo studies

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