Urocortin-2 a potential treatment target for HFpEF

An animal study showed that the urocortin-2/corticotropin-releasing-hormone-receptor (CRHR)-2 system is altered in animals with heart failure with preserved ejection fraction (HFpEF) compared with healthy animals. Treatment with urocortin-2 may attenuate left ventricular remodelling in these animals and improve cardiac function.

“HFpEF has been characterised by rising prevalence and a shortage of therapeutic options,” said Ms Inês Vasconcelos (Medicine University of Porto, Portugal). Urocortins are peptides of the corticotropin-releasing factor (CRF) family and the urocortin-2-binding CRHR2 is detected in the myocardium and vasculature [1]. Additionally, urocortin peptides have beneficial haemodynamic and renal effects in animals with heart failure with preserved ejection fraction (HFrEF) [2]. The current study used ZSF1 animals (Zucker fatty and spontaneously hypertensive; ZSF-lean n=26; ZSF-obese n=28) that were subjected to either urocortin-2 therapy or vehicle therapy for 12 weeks [3]. Hereafter, haemodynamic and other analyses were performed.

Morphometric analysis showed that obese animals treated with urocortin-2 had a slightly lower mean left ventricular mass than non-treated obese animals. Additionally, histologic analysis revealed that obese animals on urocortin-2 had a slightly decreased cardiomyocyte cross-sectional area and reduced fibrosis compared with obese animals, indicating an anti-hypertrophic effect of urocortin-2. Furthermore, the haemodynamic analysis demonstrated that the increased end-diastolic pressure in obese animals was significantly reduced in animals treated with urocortin-2 (P<0.01). Also, urocortin-2 treatment resulted in a slight reduction in end-systolic pressure. In contrast, the echocardiographic and functional analyses did not show marked differences between animals who were treated with urocortin-2 and the non-treated animals.

From a molecular biology standpoint, the authors detected a significant decrease of urocortin-2 (P=0.0291) and its receptor (P=0.0288) in obese animals compared with lean animals, which was negatively correlated with left atrium volume and E/E’ ratio, suggesting a dysfunction in the urocortin-2/CRHR2 system of the animals with HFpEF. Finally, reductions in BNP, TNF-α, and Col3A1 were reported in animals treated with urocortin-2, which may be linked to improved cardiac function and anti-inflammatory and anti-fibrotic effects.

“The urocortin-2/CRHR2 system is altered in experimental HFpEF, and treatment with urocortin-2 attenuates left ventricular remodelling in animals with HFpEF,” concluded Ms Vasconcelos.

1. Kuperman Y, Chen A. Trends Endocrinol Metab. 2008;19(4):122–129.
2. Rademaker MT, Richards AM. Am Clin Chim Acta. 2017;474:76–87.
3. Vasconcelos I, et al. Therapeutic effects of urocortin-2 in Heart Failure with preserved Ejection Fraction. Basic & Translational Late-Breaking Science, Heart Failure 2022, 21–24 May, Madrid, Spain.

 

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Posted on 28 July 2022