Systemic and brown adipose tissue-specific depletion of PCPE-1 ameliorated left ventricular fibrosis and diastolic dysfunction in obese and aged mouse models of HFpEF.
Does PCPE-1 depletion ameliorate left ventricular fibrosis and diastolic dysfunction in aging and obesity-related HFpEF mouse models?
PCPE-1, a pro-fibrotic protein derived from brown adipose tissue, promotes cardiac fibrosis and diastolic dysfunction in aging and obesity, highlighting it as a potential therapeutic target for HFpEF.
Heart failure with preserved ejection fraction (HFpEF) is a multifactorial disease that develops in several clinical settings. Despite its complex pathogenesis, evidence indicates a central role for fibrosis in the progression of left ventricular (LV) diastolic dysfunction (LVDD). Through exploratory research into brown adipose tissue (BAT)-derived adipokines (BATokines), we identified a secreted-type pro-fibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), whose expression increased in BAT with aging. PCPE-1 promotes the cleavage of procollagens and is a critical initiator of fibrillogenesis. This molecule was increased in the plasma of aged mice. In addition to aging, dietary obesity led to an increase in PCPE-1 expression in the LV of mice. Both systemic and BAT-specific PCPE-1 depletion ameliorated LV fibrosis and LVDD in the obese HFpEF model. Our data also showed that age-associated LVDD was ameliorated in the systemic PCPE-1 knockout mouse model fed with a normal chow diet. Conversely, the overexpression of PCPE-1 expression in BAT was shown to lead to aggravation of LV fibrosis and LVDD. Mechanistically, we found reactive oxygen species (ROS)/DNA damage/c-Fos/c-Jun signaling resulted in an increased production of PCPE-1 in brown adipocytes. These results indicate PCPE-1 may represent a druggable target for aging- and obesity-related HFpEF.
Hsiao et al. (Thu,) conducted a other in Heart failure with preserved ejection fraction (HFpEF). PCPE-1 depletion vs. Littermate controls was evaluated on Left ventricular fibrosis and diastolic dysfunction. Systemic and brown adipose tissue-specific depletion of PCPE-1 ameliorated left ventricular fibrosis and diastolic dysfunction in obese and aged mouse models of HFpEF.