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. 2021 Feb 1:266:118877.
doi: 10.1016/j.lfs.2020.118877. Epub 2020 Dec 10.

Sacubitril/valsartan treatment relieved the progression of established pulmonary hypertension in rat model and its mechanism

ShuangYe Liu  1 , Ya Wang  1 , Shuai Lu  2 , Jing Hu  1 , XiaoHui Zeng  1 , WenHu Liu  1 , Yan Wang  3 , ZhaoHui Wang  4
Affiliations

Sacubitril/valsartan treatment relieved the progression of established pulmonary hypertension in rat model and its mechanism

ShuangYe Liu et al. Life Sci. .

Abstract

Aims: Pulmonary hypertension (PH) is a fatal disease identified by progressive elevated pulmonary arterial pressure, which neurohormonal activation is a notable contributor to its development. Sacubitril/valsartan is a complex of sacubitril [via enhancing the natriuretic peptide (NP) system] and valsartan [via blocking the renin-angiotensin-aldosterone system (RAAS)]. Regulation of the two neurohormonal system had been shown to attenuate PH. This study was to explore the role of sacubitril/valsartan in both monocrotaline (MCT)-induced and hypoxia-induced rat models and the underlying mechanism.

Main methods: The rats were treated with MCT or hypoxic environment for 14 days, after that sacubitril/valsartan were given for another 14 days. Hemodynamic measurements and histological assessments were performed. The expression of NPs was measured using RT-PCR and ELISA, while the protein level of natriuretic peptide receptors (NPRs) and AT1 receptor were detected by western blot, the concentrations of cGMP, IL-1β, IL-6, TNF-α and TGF-β1 were tested by ELISA.

Key findings: We found that sacubitril/valsartan significantly improved the hemodynamic and histological data of two PH models. Sacubitril/valsartan suppressed the protein expression of AT1 receptor (P < 0.05). The intervention increased the expression of ANP and CNP (P< 0.05) and therefore upregulated the protein expression of NPRs (P < 0.05), raised the concentration of cGMP (P < 0.05). In addition, the treatment reduced the concentration of IL-1β, IL-6 and TNF-α (P < 0.05) but have no effects on TGF-β1.

Significance: Sacubitril/valsartan alleviated PH in MCT-induced and hypoxia-induced rat models by inhibiting the activated RAAS, promoting ANP/NPR-A/cGMP and CNP/NPR-B/cGMP pathway, restoring the NPR-C signaling and the anti-inflammatory effects.

Keywords: Natriuretic peptide system; Pulmonary hypertension; Renin-angiotensin-aldosterone system; Sacubitril/valsartan; cGMP.

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