Therapeutic effect of Fuzheng Yixin decoction on cardiac insufficiencythe soluble guanylyl cyclase-cyclic guanosine monophosphate-protein kinase G pathway in a doxorubicin-induced dilated cardiomyopathy rat model.

FZYX treatment alleviated body weight loss in doxorubicin-induced DCM rats.

• Sprague-Dawley rats were intraperitoneally injected with doxorubicin for 6 consecutive weeks to induce DCM.
• Rats were subsequently treated intragastrically with low-dose FZYX, high-dose FZYX, or captopril for 4 weeks.
• Body weight loss was identified as one of the measurable outcomes of DCM that was alleviated by FZYX intervention.

FZYX inhibited ventricular dilatation and restored impaired heart function in DCM rats.

• Transthoracic echocardiography was used to evaluate cardiac functional parameters.
• Serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were measured as a marker of cardiac insufficiency.
• FZYX treatment at both low and high doses was associated with restoration of impaired heart function compared to untreated DCM animals.
• Captopril was used as a positive control comparator.

FZYX restored ruptured sarcomeres, mitochondrial damage, and pathological myocardial changes in DCM rats.

• Haematoxylin and eosin (H&E) and Masson staining were used to assess histopathological changes.
• Electron microscopy was employed to evaluate ultrastructural changes including sarcomere integrity and mitochondrial morphology.
• Immunohistochemistry was also used as part of the efficacy evaluation.
• Both structural and ultrastructural damage induced by doxorubicin were attenuated by FZYX treatment.

FZYX reduced collagen deposition in myocardial tissue of DCM rats.

• Masson staining was used to quantify collagen deposition as a marker of cardiac fibrosis.
• Collagen deposition is a hallmark of pathological remodeling in dilated cardiomyopathy.
• FZYX intervention reduced this fibrotic change in the myocardium.

Transcriptomic and non-targeted metabolomic analyses revealed that FZYX regulated sGC-cGMP-PKG pathway-related genes and metabolites.

• Differentially expressed genes and metabolites in myocardial tissue were identified following FZYX intervention.
• FZYX regulated expression of pathway-related genes Nppa (natriuretic peptide precursor A) and Nppb (natriuretic peptide precursor B).
• Regulated metabolites included cGMP, 5'-guanylic acid, and adenosine.
• Ultra-high-performance liquid chromatography Q-exactive mass spectrometry was utilized to obtain mass spectrum data for FZYX characterization.

FZYX suppressed the expression of Nppa and Nppb while increasing the expression of sGC, PKG, and PKG-1α in DCM rats.

• Quantitative polymerase chain reaction (qPCR) and Western blotting (WB) were used to verify molecular targets.
• FZYX suppressed the expression of Nppa and Nppb, which are markers of cardiac stress and heart failure.
• FZYX increased the expression of soluble guanylyl cyclase (sGC), which led to further increases in the levels of PKG and PKG-1α.
• These molecular findings were consistent with the transcriptomic and metabolomic results.

The cardioprotective effect of FZYX may be mediated through restoration of the sGC-cGMP-PKG signaling pathway.

• The sGC-cGMP-PKG pathway was identified as a key mechanistic pathway through integrated transcriptomic and metabolomic analysis.
• Upregulation of sGC led to downstream increases in cGMP and PKG activity.
• This pathway restoration correlated with observed improvements in cardiac structure and function.
• The authors propose that FZYX 'may provide a new strategy for clinical application against DCM.'