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，同时由于挽救生命的疗法提高了存活率，至少收缩期心衰的患病率也在增加。尽管治疗效果最佳，但心力衰竭患者的病情进展与高死亡率有关。在65岁的受试者中，心力衰竭仍然是入院的首要原因。针对心力衰竭流行的明显解决方案是通过专门针对参与向心力衰竭过渡的机械性靶点的治疗来预防新的心力衰竭发作。盐皮质激素受体(MR)及其天然配体--醛固酮(ALDO)在心脏和动脉重塑中起重要作用，但其潜在作用尚不清楚。强烈推荐MR拮抗剂用于治疗收缩症状性心力衰竭，并有可能用于射血分数保留的心力衰竭。然而，不良反应限制了它们在临床实践中的使用。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。这可能参与了心力衰竭的MR激活，但这一点从未被探索过。这项申请的法国和德国合作伙伴已经确定中性粒细胞明胶酶相关的Lipocalin(NGAL)、Galectin-3(Gal-3)和特定的非编码RNA，如microRNAs(MiRNAs)是高度集中的靶标，控制着MR介导的下游关键的HF机制。因此，干扰参与MR上游和/或下游激活的机制通路可能为MRAS提供治疗的替代方案。

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.