Key result
Guanylyl cyclase C hyperactivation drives pathological hypertrophy and systolic dysfunction, rescued by NFAT inhibition.
Why the study?
Guanylyl cyclase C regulates fluid balance and tumorigenesis in the gastrointestinal tract, with activating GUCY2C mutations linked to congenital secretory diarrhea and dysmotility, while its role in cardiac remodeling and dysfunction was uncharacterized.
Does inhibiting NFAT improve cardiac function and attenuate pathological cardiac remodeling in mice harboring a hyperactivating mutation in guanylyl cyclase C (GC-C)?
Does inhibiting NFAT improve cardiac function and attenuate pathological cardiac remodeling in mice harboring a hyperactivating mutation in guanylyl cyclase C (GC-C)?
Hyperactivation of intestinal guanylyl cyclase C indirectly drives pathological cardiac hypertrophy and heart failure in mice via electrolyte and fluid imbalance, which can be rescued by inhibiting the NFAT pathway.
Supports GC-C hyperactivation models of secretory diarrhea; leaves open targeted therapies pending human validation.
Receptor guanylyl cyclases are membrane-associated proteins that mediate intracellular signaling by converting GTP to the second messenger cGMP. Guanylyl cyclase C (GC-C) is mainly expressed on the apical membrane of intestinal epithelial cells. In the gastrointestinal tract, GC-C regulates fluid balance and tumorigenesis. Activating mutations in GUCY2C are associated with congenital secretory diarrhea and dysmotility. In the present study, we demonstrate that mice harboring a hyperactivating mutation in GC-C display pathological cardiac hypertrophy and increased atrial blood pressure. Mice hearts display no detectable GC-C expression, yet exhibit impaired systolic function, interstitial fibrosis, and increased cardiomyocyte apoptosis, suggesting an indirect systemic mechanism. The constitutive activation of GC-C aggravates pathological cardiac remodeling and heart failure in response to electrolyte and fluid imbalance, possibly through the PKA-GSK3β-NFAT axis. Inhibiting NFAT in hyperactive GC-C mice rescues cardiac functions. These data implicate a previously uncharacterized role for GC-C in maladaptive cardiac hypertrophy and dysfunction.
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Prabhashankar et al. (2026) studied Pathological cardiac hypertrophy and dysfunction. Guanylyl cyclase C (GC-C) hyperactivating mutation and NFAT inhibition was evaluated on Pathological cardiac hypertrophy, systolic function, interstitial fibrosis, and cardiomyocyte apoptosis. Guanylyl cyclase C hyperactivation in mice drives pathological cardiac hypertrophy, fibrosis, and systolic dysfunction via the PKA-GSK3β-NFAT axis, which is rescued by NFAT inhibition.
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