Regulation, Diagnostics and Therapy focusing on the mineralocorticoidreceptor involved in cardiac remodelling

由于人口老龄化，心力衰竭（HF）的发病率正在增加，而由于挽救生命的治疗提高了生存率，至少收缩期HF的患病率也在增加。尽管有最佳治疗，心衰患者仍会经历与高死亡率相关的疾病进展。心衰仍然是bb0 ~ 65岁患者住院的首要原因。解决HF流行的一个显而易见的方法是，通过专门针对参与向HF转变的机制靶点的治疗来预防新发HF。矿物皮质激素受体（MR）及其天然配体醛固酮（Aldo）在心脏和动脉重塑过程中发挥重要作用，但其潜在作用尚不清楚。MR拮抗剂被强烈推荐用于治疗收缩期症状性心衰，并可能用于保留射血分数的心衰。然而，其副作用限制了其在临床实践中的应用。上游，MR的表达水平和活性受遗传（功能多态性）和表观遗传（miRNA， DNA甲基化）特征的调节。这可能参与HF的MR激活，但这从未被探索过。该应用的法国和德国合作伙伴已经确定中性粒细胞明胶酶相关脂钙蛋白（NGAL），半乳糖凝集素-3 （Gal-3）和特异性非编码rna，如microrna （miRNAs）作为高度集中的靶点，控制下游关键MR介导的HF机制。因此，干扰上游和/或下游MR激活的机制通路可能为mra的治疗提供替代方案。

The incidence of heart failure (HF) is increasing because of ageing of the population, while the prevalence at least of systolic HF is also increasing because of improved survival, as a result of life saving therapies. Despite optimal therapy, patients with HF experience disease progression associated with high mortality rates. HF is still the first cause of hospital admission in subjects aged>65 years. The obvious solution for HF epidemics is to prevent new onset HF with therapies directed specifically to mechanistic targets that are involved in the transition to HF. The mineralocorticoid receptor (MR) and its natural ligand, the hormone Aldosterone (Aldo), play important roles during cardiac and arterial remodeling, but the underlying effects are still not understood. MR antagonists are highly recommended for treatment of systolic symptomatic HF, and potentially for HF with preserved ejection fraction. However, adverse effects limit their use in clinical practice. Upstream, MR expression level and activity are modulated by genetic (functional polymorphisms) and epigenetic (miRNA, DNA methylation) features. This could participate to MR activation in HF but this has never been explored. The French and German Partners of this application have identified Neutrophil Gelatinase-Associated Lipocalin (NGAL), Galectin-3 (Gal-3) and specific non-coding RNAs such as microRNAs (miRNAs) as highly focused targets controlling downstream key MR mediated HF mechanisms. Therefore, interfering with mechanistic pathways involved in upstream and/or downstream MR activation may provide therapeutic alternatives to MRAs.