Targeted proteomic analyses during combined angiotensin-converting enzyme inhibitor and mineralocorticoid receptor antagonist administration (CARDALIS®) in healthy dogs
Jessica L Ward, Jessica Goodman, Thomas Blondel, Christopher Zdyrski, Elizabeth Manson, Maria Merodio, Ryan P Lamers, Karin Allenspach, Emilie Guillot, Jonathan P MochelAbstract
Background
The effects of renin–angiotensin–aldosterone system (RAAS) inhibitors on proteomic biomarkers of cardiovascular disease in dogs remain poorly characterized.
Hypothesis/Objectives
To evaluate the effect of RAAS activation and treatment with a combination of benazepril and spironolactone on circulating proteomic biomarkers in healthy dogs.
Animals
Eighteen healthy beagle dogs.
Methods
Prospective experimental study. Dogs were fed a low-sodium diet to induce RAAS activation and randomly assigned to 1 of 3 dosing regimens for 14 days: (1) benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q24h (label dose); (2) benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q12h; or (3) benazepril 0.5 mg/kg + spironolactone 4 mg/kg PO q12h. Plasma samples were collected at multiple time points, and the concentrations of 177 unique proteins were quantified using multiplexed proximity extension assay technology via the Olink Target 96 Inflammation and Cardiovascular II panels. Differences between sampling days and groups were assessed using linear mixed models.
Results
Renin–angiotensin–aldosterone system activation was associated with downregulation of proteins associated with cardioprotection, adaptive immunity, and tissue repair (eg, ACE2, FGF-5, CCL4, and MMP-10; P < .05 for all comparisons). Treatment with benazepril and spironolactone led to upregulation of adaptive immune proteins (eg, CCL4, TSLP) and proteins with cardioprotective functions (eg, ACE2). Dose-related differences were observed for a subset of biomarkers.
Conclusions and clinical importance
In this experimental model of RAAS activation, benazepril/spironolactone combination therapy exerts effects on markers of inflammation and fibrosis in dogs.