CRD-733, a Novel PDE9 (Phosphodiesterase 9) Inhibitor, Reverses Pressure Overload–Induced Heart Failure
| Autor: | Robert M. Blanton, Kelly Tam, Gregory L. Martin, Michael E. Mendelsohn, Daniel M. Bloomfield, Richard H. Karas, Daniel A. Richards, Peiwen Liu, Suchita Pande, Mark Aronovitz |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Phosphodiesterase Inhibitors medicine.drug_class Heart Ventricles Pulmonary Edema Constriction Pathologic 030204 cardiovascular system & hematology Pharmacology Article Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Natriuretic peptide medicine Animals Heart Atria Phosphorylation Receptor Cyclic GMP Lung Cyclic guanosine monophosphate Neprilysin Aorta Cyclic GMP-Dependent Protein Kinase Type I 030304 developmental biology Heart Failure Pressure overload 0303 health sciences Ventricular Remodeling business.industry Phosphodiesterase Heart Stroke Volume Organ Size medicine.disease Fibrosis chemistry 3' 5'-Cyclic-AMP Phosphodiesterases Heart failure Hypertrophy Left Ventricular Collagen Carrier Proteins Cardiology and Cardiovascular Medicine business cGMP-dependent protein kinase |
| Zdroj: | Circ Heart Fail |
| ISSN: | 1941-3297 1941-3289 |
| Popis: | Background: Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies. Here, we explore the effects of chronic PDE9 inhibition with CRD-733 in the mouse transverse aortic constriction pressure overload HF model. Methods: Adult male C57BL/6J mice were subjected to transverse aortic constriction and developed significant left ventricular (LV) hypertrophy after 7 days ( P Results: CRD-733 treatment reversed existing LV hypertrophy compared with vehicle ( P P =0.009), and attenuated left atrial dilation ( P P =0.037) compared with vehicle, while lung weights, a surrogate for pulmonary edema, were reduced to sham levels. Chronic CRD-733 treatment increased plasma cGMP levels compared with vehicle ( P 273 of cardiac myosin binding protein-C, a cGMP-dependent protein kinase I phosphorylation site. Conclusions: The PDE9 inhibitor, CRD-733, improves key hallmarks of HF including LV hypertrophy, LV dysfunction, left atrial dilation, and pulmonary edema after pressure overload in the mouse transverse aortic constriction HF model. Additionally, elevated plasma cGMP may be used as a biomarker of target engagement. These findings support future investigation into the therapeutic potential of CRD-733 in human HF. |
| Databáze: | OpenAIRE |
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