Altara Raffaele, Zouein Fouad A, Brandão Rita Dias, Bajestani Saeed N, Cataliotti Alessandro, Booz George W
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
KG Jebsen Center for Cardiac Research, Oslo, Norway.
Front Cardiovasc Med. 2018 Feb 21;5:11. doi: 10.3389/fcvm.2018.00011. eCollection 2018.
Standard therapies for heart failure with preserved ejection fraction (HFpEF) have been unsuccessful, demonstrating that the contribution of the underlying diastolic dysfunction pathophysiology differs from that of systolic dysfunction in heart failure and currently is far from being understood. Complicating the investigation of HFpEF is the contribution of several comorbidities. Here, we selected three established rat models of diastolic dysfunction defined by three major risk factors associated with HFpEF and researched their commonalities and differences. The top differentially expressed genes in the left ventricle of Dahl salt sensitive (Dahl/SS), spontaneous hypertensive heart failure (SHHF), and diabetes 1 induced HFpEF models were derived from published data in Gene Expression Omnibus and used for a comprehensive interpretation of the underlying pathophysiological context of each model. The diversity of the underlying transcriptomic of the heart of each model is clearly observed by the different panel of top regulated genes: the diabetic model has 20 genes in common with the Dahl/SS and 15 with the SHHF models. Advanced analytics performed in Ingenuity Pathway Analysis (IPA) revealed that Dahl/SS heart tissue transcripts triggered by upstream regulators lead to dilated cardiomyopathy, hypertrophy of heart, arrhythmia, and failure of heart. In the heart of SHHF, a total of 26 genes were closely linked to cardiovascular disease including cardiotoxicity, pericarditis, ST-elevated myocardial infarction, and dilated cardiomyopathy. IPA Upstream Regulator analyses revealed that protection of cardiomyocytes is hampered by inhibition of the ERBB2 plasma membrane-bound receptor tyrosine kinases. Cardioprotective markers such as natriuretic peptide A (), heat shock 27 kDa protein 1 (), and angiogenin () were upregulated in the diabetes 1 induced model; however, the model showed a different underlying mechanism with a majority of the regulated genes involved in metabolic disorders. In conclusion, our findings suggest that multiple mechanisms may contribute to diastolic dysfunction and HFpEF, and thus drug therapies may need to be guided more by phenotypic characteristics of the cardiac remodeling events than by the underlying molecular processes.
射血分数保留的心力衰竭（HFpEF）的标准治疗方法一直未取得成功，这表明潜在的舒张功能障碍病理生理学与心力衰竭中收缩功能障碍的病理生理学不同，目前人们对此还远未了解。多种合并症的存在使HFpEF的研究变得复杂。在此，我们选择了三种由与HFpEF相关的三个主要风险因素定义的已建立的舒张功能障碍大鼠模型，并研究了它们的异同。Dahl盐敏感（Dahl/SS）、自发性高血压心力衰竭（SHHF）和糖尿病1诱导的HFpEF模型左心室中差异表达最显著的基因来自基因表达综合数据库（Gene Expression Omnibus）中的已发表数据，并用于全面解读每个模型潜在的病理生理背景。通过不同的顶级调控基因面板可以清楚地观察到每个模型心脏潜在转录组的多样性：糖尿病模型与Dahl/SS模型有20个共同基因，与SHHF模型有15个共同基因。在 Ingenuity Pathway Analysis（IPA）中进行的高级分析表明，上游调节因子触发的Dahl/SS心脏组织转录本会导致扩张型心肌病、心脏肥大、心律失常和心力衰竭。在SHHF心脏中，共有26个基因与心血管疾病密切相关，包括心脏毒性、心包炎、ST段抬高型心肌梗死和扩张型心肌病。IPA上游调节因子分析表明，ERBB2质膜结合受体酪氨酸激酶的抑制会阻碍心肌细胞的保护。在糖尿病1诱导的模型中，利钠肽A、热休克27 kDa蛋白1和血管生成素等心脏保护标志物上调；然而，该模型显示出不同的潜在机制，大多数受调控基因参与代谢紊乱。总之，我们的研究结果表明，多种机制可能导致舒张功能障碍和HFpEF，因此药物治疗可能需要更多地以心脏重塑事件的表型特征为指导，而不是以潜在的分子过程为指导。
