Probenecid treatment improves outcomes in a novel mouse model of peripartum cardiomyopathy

Abstract

Probenecid has been used for decades in the treatment of gout but recently has also been found to improve outcomes in patients with heart failure via stimulation of the transient receptor potential vanilloid 2 (TRPV2) channel in cardiomyocytes. This study tested the use of probenecid on a novel mouse model of peripartum cardiomyopathy (PPCM) as a potential treatment option. A human mutation of the human heat shock protein 20 (Hsp20-S10F) in mice has been recently shown to result in cardiomyopathy, when exposed to pregnancies. Treatment with either probenecid or control sucrose water was initiated after the first pregnancy in both wild type and Hsp20-S10F mice. Serial echocardiography was performed during subsequent pregnancies and hearts were collected after the third pregnancies for staining and molecular analysis. Hsp20-S10F mice treated with probenecid had decreased mortality, hypertrophy, TRPV2 expression and molecular parameters of heart failure. Probenecid treatment also decreased apoptosis as evidenced by an increase in the level of Bcl-2/Bax. Probenecid improved survival in a novel mouse model of PPCM and may be an appropriate therapy for humans with PPCM as it has a proven safety and tolerability in patients with heart failure.

Repurposing Probenecid for the Treatment of Heart Failure (Re-Prosper-HF): a study protocol for a randomized placebo-controlled clinical trial

“…Specifically, murine ischemic models demonstrated dramatically increased contractility after treatment with probenecid that was inversely proportional to the degree of baseline dysfunction, consistent with higher expression of myocardial TRPV2 under stress conditions [9]. Other studies, including a murine model of peripartum cardiomyopathy and in vivo porcine model documented similar increases in contractility without increased arrhythmias or mortality [10,11].…”

Transient receptor potential vanilloid (TRPV) channels: Basal properties and physiological potential

“…It is also expected to be a new therapeutic target in the fields of cardiology and neurology. In a mouse model of peripartum cardiomyopathy, probenecid treatment decreased mortality, hypertrophy, and molecular parameters of heart failure (Onusko et al 2020). In a clinical trial, probenecid treatment improved cardiac function accompanied by heart failure with reduced ejection fraction (Robbins et al 2018).…”

Beyond Hot and Spicy: TRPV Channels and their Pharmacological Modulation

“…Even though activation of TRPV2 by probenecid needs high concentration, the selectivity profile towards TRPV1, TRPV3, TRPV4 and TRPM8 is sufficient for in vitro discrimination [138]. Although probenecid activates TRPV2, several studies suggest positive outcomes in models of cardiomyopathy [139,140]. The authors suggest that increased influx of Ca 2+ by activation of TRPV2 leads to increased contractility and increased ejection fraction [139,140].…”

“…Although probenecid activates TRPV2, several studies suggest positive outcomes in models of cardiomyopathy [139,140]. The authors suggest that increased influx of Ca 2+ by activation of TRPV2 leads to increased contractility and increased ejection fraction [139,140]. For inhibition of TRPV2 channels the histamine releasing inhibitor tranilast can be used [141].…”