Transforming growth factor-ß downregulates sGC subunit expression in pulmonary artery smooth muscle cells via MEK and ERK signaling.

TGFß activation during newborn lung injury decreases the expression of pulmonary artery smooth muscle cell (PASMC)-soluble guanylate cyclase (sGC), a critical mediator of nitric oxide signaling. Using a rat PASMC line (CS54 cells), we determined how TGFß downregulates sGC expression. We found that TGFß decreases sGC expression through stimulating its type I receptor; TGFß type I receptor (TGFßR1) inhibitors prevented TGFß-1-mediated decrease in sGCα1 subunit mRNA levels in the cells. However, TGFßR1-Smad mechanisms do not regulate sGC; effective knockdown of Smad2 and Smad3 expression and function did not protect sGCα1 mRNA levels during TGFß-1 exposure. A targeted small-molecule kinase inhibitor screen suggested that MEK signaling regulates sGC expression in TGFß-stimulated PASMC. TGFß activates PASMC MEK/ERK signaling; CS54 cell treatment with TGFß-1 increased MEK and ERK phosphorylation in a biphasic, time- and dose-dependent manner. Moreover, MEK/ERK activity appears to be required for TGFß-mediated sGC expression inhibition in PASMC; MEK and ERK inhibitors protected sGCα1 mRNA expression in TGFß-1-treated CS54 cells. Nuclear ERK activity is sufficient for sGC regulation; heterologous expression of a nucleus-retained, constitutively active ERK2-MEK1 fusion protein decreased CS54 cell sGCα1 mRNA levels. The in vivo relevance of this TGFß-MEK/ERK-sGC downregulation pathway is suggested by the detection of ERK activation and sGCα1 protein expression downregulation in TGFß-associated mouse pup hyperoxic lung injury, and the determination that ERK decreases sGCα1 protein expression in TGFß-1-treated primary PASMC obtained from mouse pups. These studies identify MEK/ERK signaling as an important pathway by which TGFß regulates sGC expression in PASMC.

The efficacy and safety of soluble guanylate cyclase stimulators in patients with heart failure: A systematic review and meta-analysis.

BACKGROUND: Several randomized controlled trials (RCTs) have been investigated the benefits of soluble guanylate cyclase (sGC) stimulators in the treatment of heart failure, but a comprehensive evaluation is lacking. We performed a meta-analysis to evaluate the efficacy and safety of oral sGC stimulators (vericiguat and riociguat) in patients with heart failure. METHODS: Studies were searched and screened in PubMed, Embase, and Cochrane Library. Eligible RCTs were included that reported mortality, the change of EuroQol Group 5-Dmensional Self-report Questionnaire (EQ-5D) US index, N-terminal pro-B-type natriuretic peptide (NT-proBNP), or serious adverse events (SAEs). Relative risk or weight mean difference (WMD) was estimated using fixed effect model or random effect model. Analysis of sensitivity and publication bias was conducted. RESULTS: Five trials with a total of 1200 patients were included. sGC stimulators had no impact on the mortality (1.25; 95% confidence interval 0.50-3.11) and significantly improved EQ-5D US index (0.04; 95% confidence interval 0.020-0.05). Furthermore, in comparison with control group, NT-proBNP was statistically decreased in riociguat group (-0.78; 95% confidence interval -1.01 to -0.47), but not in vericiguat group (0.04, 95% confidence interval -0.18 to 0.25). There were not obverse differences in SAEs between sGC stimulators and control groups (0.90; 95% confidence interval 0.72-1.12). CONCLUSION: Our meta-analysis suggests that sGC stimulators could improve the quality of life in patients with heart failure with good tolerance and safety, but their long-term benefits need to be observed in the future. sGC stimulators are likely to be promising add-on strategies for the treatment of heart failure.

The evolution of prostacyclins in pulmonary arterial hypertension: from classical treatment to modern management.

Prostacyclins for the treatment of pulmonary arterial hypertension (PAH) have historically been covered under the insurance medical benefit because they require durable medical equipment and are administered by an intravenous, subcutaneous, or inhalation route. However, more treatment options that target the prostacyclin pathway have become available. As the number and type of options expand, an improved understanding of these drugs will aid managed care decision makers in evaluating new treatment options and making clinically sound and cost-effective treatment decisions. PAH is a progressive disease of pulmonary vascular remodeling that increases pulmonary vascular resistance and often results in right-side heart failure and death if left untreated. Adverse event profiles, the complexity of administration modalities, and potential complications must be considered when administering prostacyclin therapy. Traditional modes of administration, with their potential challenges and complications, may have contributed to the unmet need for an oral agent. Another consideration for managed care decision makers is that oral agents are generally covered under the insurance pharmacy benefit. Access to oral medications with long-term outcomes data, as well as the improved convenience of oral therapy, may help patients with PAH maximize function by maintaining a more convenient and consistent therapeutic regimen.