Soluble guanylate cyclase as a therapeutic target in heart failure: modulation of oxidative stress and cardiac remodeling pathways with potential implications for heart failure therapy

Abstract

Heart failure (HF) results from multiple pathological stressors, including pressure and volume overload, and is characterized by dysregulation of multiple cardiac signaling pathways. In particular, the nitric oxide–soluble guanylate cyclase–cyclic guanosine monophosphate (NO–sGC–cGMP) pathway represents one of the potential therapeutic targets, and its modulation may influence oxidative stress and maladaptive cardiac remodeling, which are markedly altered in HF and contribute to disease progression. Pharmacological activation of this pathway via sGC stimulators has emerged as a promising strategy to counteract HF progression.

To investigate the effects of sGC stimulation, we used male hypertensive Ren-2 transgenic (TGR) rats (n = 16) and TGR rats with aortocaval fistula (ACF)- induced HF (TGR-ACF, n = 34) to examine the impact of dual pressure and volume overload in the pathophysiology of HF. Hypertensive TGR rats were treated with the sGC stimulator BAY 41-8543 (3 mg/kg/day) for 30 weeks, while normotensive Hannover Sprague-Dawley rats (n = 8) served as controls. At the study endpoint (40 weeks of age), left ventricular tissue was collected for molecular and histological analyses.

In hypertensive TGR rats, sGC stimulation significantly improved survival and upregulated key antioxidant proteins (SOD1, CH10, ACSF2, NDUS1, DHE3, GSTM2, and PCCA), suggesting protection against oxidative stress. Moreover, sGC stimulation increased the protein expression of extracellular matrix markers (MMP-2, TGF-β, and SMAD2/3), while Masson's trichrome staining revealed attenuated collagen deposition in pressure- and volume-overloaded rats, suggesting a complex interplay in extracellular matrix regulation. Notably, almost all untreated TGR-ACF rats suffering from dual pressure and volume overload did not survive, precluding direct evaluation of sGC stimulators in advanced HF.

These findings support the therapeutic potential of sGC stimulation in HF, primarily through antioxidative mechanisms, while its effects on cardiac remodeling warrant further investigation.