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.
Highlights
Heart failure remains one of the leading causes of mortality and morbidity worldwide, despite great improvements in treatments for associated diseases
By measuring the levels of vascular endothelial growth factor C (VEGF-C), VEGF receptor 3 (VEGFR3), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), using western blots, and examining the colocalization of lymphatic vessels and macrophages, using immunofluorescence, we explored the changes that occurred in the cardiac lymphatic system and the role played by LCZ696 in transverse aortic constriction (TAC) mice
The cardiac function was significantly impaired in the TAC alone group but was ameliorated in the LCZ696 treatment group. Heart function indicators, such as left ventricular internal dimension in systole (LVIDS), left ventricular internal dimension in diastole (LVIDD), left ventricular systolic posterior wall thickness (LVPWS), LVPWD, interventricular septal end-systolic thickness (IVSS), interventricular septal enddiastolic thickness (IVSD), ejection fraction (EF)%, and FS%, were significantly improved in the LCZ696 treatment group compared with the untreated group (Table 2)
Summary
Heart failure remains one of the leading causes of mortality and morbidity worldwide, despite great improvements in treatments for associated diseases. Previous studies have demonstrated that LCZ696, which is an angiotensin receptor-neprilysin inhibitor (ARNI), improved cardiac function, with the attenuation of fibrosis, when used to treat several types of heart failure with reduced ejection fractions [1]. In the PARAMOUNT study (a prospective comparison between an ARNI and an angiotensin receptor blocker (ARB) for the management of heart failure with preserved ejection fraction (HFpEF)), LCZ696 treatment reduced the serum levels of the N-terminal, pro-B-type, natriuretic peptide, compared with valsartan treatment after 12 weeks, and was well-tolerated when used for the treatment of HFpEF [2]. LCZ696 treatment significantly ameliorated cardiac hypertrophy, inflammation, and vascular endothelial dysfunction in highsalt loaded spontaneously hypertensive rats compared with valsartan treatment [4]. LCZ696 treatment improved isoproterenol-induced cardiac fibrosis, BioMed Research International but not hypertrophy, in rats [6]. LCZ696 treatment improved isoproterenol-induced cardiac fibrosis, BioMed Research International but not hypertrophy, in rats [6]. e effects of LCZ696 on pressure overload-induced cardiac hypertrophy remain unclear, and the possible potential mechanisms are unknown
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