Sacubitril/Valsartan attenuates progression of diabetic cardiomyopathy through immunomodulation properties: an opportunity to prevent progressive disease.

IF 8.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Narainrit Karuna, Lauren Kerrigan, Kevin Edgar, Mark Ledwidge, Ken McDonald, David J Grieve, Chris J Watson
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引用次数: 0

Abstract

Background and aims: Diabetic cardiomyopathy (DbCM) is recognised as a key mediator and determinant of heart failure (HF), particularly HF with preserved ejection fraction (HFpEF). Improved understanding of mechanisms underlying transition from early-stage DbCM to HFpEF will inform innovative evidence-based treatment approaches, which are urgently required to alleviate increasing disease burden. This study aimed to determine whether inhibition of neprilysin activity by Sacubitril/Valsartan in both experimental and clinical DbCM attenuates adverse remodelling through promotion of cardioprotective signalling.

Methods and results: Sacubitril/Valsartan effectively reduced plasma neprilysin activity in both diabetic patients with pre-clinical HFpEF from the PARABLE trial (baseline (Val n = 25; Sac/Val n = 35) and 3 months after treatment (Val n = 21/25; Sac/Val n = 33/35)) and DbCM (high-fat diet and streptozotocin) mice. Plasma neprilysin activity at baseline was correlated with worsening cardiac performance at 18 months indicated by left atrial stiffness index in patients (n = 44/60), whilst diastolic dysfunction and pathological remodelling in DbCM mice were improved by Sacubitril/Valsartan, but not Valsartan. snRNA-sequencing showed that progressive experimental DbCM is characterised by chronic low-grade inflammation, reflected by increased infiltration of pro-inflammatory monocytes (Ccr2+ Ly6chi) and reduction in MHC-II macrophages, which was prevented by Sacubitril/Valsartan. Informatics analysis implicated IRF7 as a central mediator of Sacubitril/Valsartan-induced immunomodulation in DbCM, whilst treatment of M2-like pro-repair macrophages with the neprilysin inhibitor, LBQ657 and Valsartan suppressed glucose-induced IRF7 expression and paracrine activation of cardiac fibroblast differentiation in vitro.

Conclusion: Immune cells are significantly involved in DbCM progression, impacting myocardial homeostasis and HF progression. Neprilysin inhibition by Sacubitril/Valsartan improved adverse cardiac remodelling in experimental DbCM through direct regulation of inflammation, highlighting immunomodulation as a novel mechanism underlying established its cardioprotective actions.

Sacubitril/缬沙坦通过免疫调节特性减缓糖尿病性心肌病的进展:一个预防疾病进展的机会
背景和目的:糖尿病性心肌病(DbCM)被认为是心力衰竭(HF)的关键介质和决定因素,特别是保留射血分数(HFpEF)的心力衰竭(HF)。提高对早期DbCM向HFpEF转变的机制的理解,将为创新的循证治疗方法提供信息,这是减轻日益增加的疾病负担所迫切需要的。本研究旨在确定Sacubitril/缬沙坦对实验性和临床DbCM中neprilysin活性的抑制是否通过促进心脏保护信号来减轻不良重构。方法和结果:Sacubitril/缬沙坦可有效降低两例临床前HFpEF糖尿病患者血浆neprilysin活性(基线(Val n = 25;Sac/Val n = 35)和治疗后3个月(Val n = 21/25;Sac/Val n = 33/35)和DbCM(高脂饮食加链脲佐菌素)小鼠。基线时血浆neprilysin活性与患者左心房僵硬指数(n = 44/60)显示的18个月时心脏功能恶化相关,而舒张功能障碍和病理重构在DbCM小鼠中被Sacubitril/缬沙坦改善,但缬沙坦没有改善。snrna测序显示,进行性实验性DbCM以慢性低度炎症为特征,表现为促炎单核细胞(Ccr2+ Ly6chi)浸润增加,MHC-II巨噬细胞减少,而Sacubitril/缬沙坦可预防这种情况。信息学分析表明,IRF7是Sacubitril/缬沙坦诱导的DbCM免疫调节的中心介质,而用neprilysin抑制剂、LBQ657和缬沙坦治疗m2样促修复巨噬细胞可抑制葡萄糖诱导的IRF7表达和体外心脏成纤维细胞分化的旁分泌激活。结论:免疫细胞明显参与DbCM进展,影响心肌稳态和心衰进展。Sacubitril/缬沙坦抑制Neprilysin通过直接调节炎症改善实验性DbCM的不良心脏重构,强调免疫调节是建立其心脏保护作用的新机制。
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来源期刊
Cardiovascular Diabetology
Cardiovascular Diabetology 医学-内分泌学与代谢
CiteScore
12.30
自引率
15.10%
发文量
240
审稿时长
1 months
期刊介绍: Cardiovascular Diabetology is a journal that welcomes manuscripts exploring various aspects of the relationship between diabetes, cardiovascular health, and the metabolic syndrome. We invite submissions related to clinical studies, genetic investigations, experimental research, pharmacological studies, epidemiological analyses, and molecular biology research in this field.
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