LCZ696, an Angiotensin Receptor-Neprilysin Inhibitor, Improves Cardiac Hypertrophy and Fibrosis and Cardiac Lymphatic Remodeling in Transverse Aortic Constriction Model Mice

Abstract

Cardiac hypertrophy and ventricular remodeling following heart failure are important causes of high mortality in heart disease patients. The cardiac lymphatic system has been associated with limited research, but it plays an important role in the improvement of myocardial edema and the promotion of fluid balance. LCZ696 is a novel combination of angiotensin and neprilysin inhibitors. Here, we studied the role played by LCZ696 during transverse aortic constriction (TAC) induced cardiac hypertrophy and changes in the lymphatic system. Mice undergoing aortic coarctation were constructed to represent a cardiac hypertrophy model and then divided into random groups that either received treatment with LCZ696 (60 mg/kg/d) or no treatment. Cardiac ultrasonography was used to detect cardiac function, and hematoxylin and eosin (H&E) and Masson staining were used to detect myocardial hypertrophy and fibrosis. The proinflammatory factors interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) were detected in the blood and heart tissues of mice. The protein expression levels of lymphatic-specific markers, such as vascular endothelial growth factor C (VEGF-C), VEGF receptor 3 (VEGFR3), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) were detected in mouse heart tissues. We also examined the colocalization of lymphatic vessels and macrophages by immunofluorescence. The results showed that LCZ696 significantly improved heart dysfunction, cardiac hypertrophy, and fibrosis and inhibited the expression of proinflammatory factors IL-6, IL-1β, and TNF-α in the circulating blood and heart tissues of mice. LCZ696 also decreased the protein expression levels of VEGF-C, VEGFR3, and LYVE-1 in mouse heart tissues, ameliorated the transport load of lymphatic vessels to macrophages, and improved the remodeling of the lymphatic system in the hypertrophic cardiomyopathy model induced by TAC.

A study of the sequential treatment of acute heart failure with sacubitril/valsartan by recombinant human brain natriuretic peptide

“…It is considered one of the protective responses to heart disease. [ 34 ] As shown in the present study, the levels of TNF-α and IL-6 were significantly reduced after treatment, and the sequential treatment group showed significantly reduced TNF-α levels. The reduction in TNF-α and IL-6 indicates that the inflammatory response of myocardial cells is reduced, and further myocardial damage is ameliorated.…”

Angiotensin receptor‐neprilysin inhibitor attenuates cardiac hypertrophy and improves diastolic dysfunction in a mouse model of heart failure with preserved ejection fraction

“…Pressure overload induces myocardial oxidative stress and apoptosis in HF, which can LCZ696 can mitigate through regulation of the Sirt3/MnSOD pathway 40 . LCZ696 inhibited the expression of proinflammatory factors such as interleukin (IL)‐1β, IL‐6, and tumour necrosis factor α (TNF‐α) in heart tissues and circulating blood in an HFrEF and hypertrophic cardiomyopathy model induced by TAC 41 . However, most of these preclinical studies have been focused on HFrEF.…”

Sacubitril/valsartan in Heart Failure and Beyond—From Molecular Mechanisms to Clinical Relevance

“…However, according to the previous basic researches, treatment with S/V decreased the circulating levels of proinflammatory cytokines, such as MMP-8, IL-6, and monocyte chemoattractant protein (MCP)-1 in ApoE2/2 mice in regard to valsartan [161]. Similarly, treatment with S/V reduced proinflammatory mediators in the blood and hearts of TAC mice [145]. In a study by Ge and colleagues [148], S/V alleviated diabetic cardiomyopathy in mice, which was an effect partially driven by its ability to inhibit inflammation.…”

“…However, MMP9 was not specifically altered with MI induction in comparison to Sham animals, neither did the applied therapies result in significant MMP9 changes. Furthermore, Ge and colleagues [145] reported that reduced cardiac fibrosis, hypertrophy, and lymphatic remodelling in mice with TAC treated with S/V was driven by its inhibitory effect on inflammatory response.…”