Regulation, Diagnostics and Therapy focusing on the mineralocorticoid receptor involved in cardiac remodelling
Final Report Abstract
In both projects from the Bauersachs and Thum teams from Hannover Medical School the importance of the mineralocorticoid receptor (MR) for cardiac remodeling was investigated. The Bauersachs team identified the macrophage MR as a crucial pathogenic player in cardiac wound repair after MI. Seven days after left coronary artery ligation, mice with myeloid cellrestricted MR deficiency compared with WT (wild type) controls displayed improved cardiac function and remodeling associated with enhanced infarct neovascularization and scar maturation. Gene expression profiling of heart-resident and infarct macrophages revealed that MR deletion drives macrophage differentiation in the ischemic microenvironment toward a phenotype outside the M1/M2 paradigm, with regulation of multiple interrelated factors controlling wound healing and tissue repair. Mechanistic and functional data suggest that inactivation of the macrophage MR promotes myocardial infarct healing through enhanced efferocytosis of neutrophils, the suppression of free radical formation, and the modulation of fibroblast activation state. Crucially, targeted delivery of MR antagonists to macrophages, with a single administration of MR antagonist-containing liposomes at the onset of MI, improved the healing response and protected against cardiac remodeling and functional deterioration, offering an effective and unique therapeutic strategy for cardiac repair. The Thum team investigated potential miRNA- mediated regulation of the Aldo-MR pathway to find novel strategies to improve mechanistic understanding and therapy of cardiac remodeling. By high-throughput screening of 2,555 miRNAs using an MR responsive stable cardiomyocyte cell line (MMTV-GFP-HL-1) miR-181a as a potential regulator of Aldo-MR pathway was identified. MiR-181a was found to downregulate the expression of Ngal (lipocalin-2), a well-established downstream effector molecule of Aldo-MR. In addition, Aldo-induced cellular hypertrophy decreased significantly upon miR-181a overexpression. Genetic miR-181 knockout in murine MI model led to deteriorated cardiac function, cardiac remodelling, and activation of Aldo-MR pathway while AAV9-mediated miR-181a overexpression improved cardiac function and deactivated Aldo-MR pathway proving a cardio-protective role of miR-181a. Global RNA sequencing of cells under Aldo treatment with/without miR-181a overexpression identified potential miR-181a targets functionally contributing to Aldo-MR pathway. Adamts1, a direct target of miR-181a, was found to be downregulated with miR-181a overexpression and upregulated with inhibition. Similar to miR-181a overexpression, siRNA-mediated inhibition of Adamts1 inhibited Aldo-MR pathway. We here show that miR-181a is a novel regulator of the Aldo-MR pathway regulating the levels of Ngal via direct targeting of Adamts1. This new insight establishes miR-181a as a factor of immense value participating in downstream networks of Aldo-MR pathway. Our in vivo studies further confirmed miR-181a as cardio-protective under MI stress. Thus, miR-181a's involvement in Aldo-MR-mediated cardiac remodelling confers it with tremendous potential to be developed further as a new therapeutic target.
Publications
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(2018) Vascular Smooth Muscle Cell Remodeling. Circ Res. 2018 Dec 7;123(12):1261-1263
Fiedler J, Thum T
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(2018). Circulating non-coding RNAs in biomarker-guided cardiovascular therapy: a novel tool for personalized medicine? Eur Heart J. 40(20):1643-1650
de Gonzalo-Calvo D, Vea A, Bär C, Fiedler J, Couch LS, Brotons C, Llorente-Cortes V, Thum T
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„Macrophage Mineralocorticoid Receptor is a Pleiotropic Modulator of Myocardial Infarct Healing“), Hypertension 2019-73:102-111
Fraccarollo D, Thomas S, Scholz CJ, Hilfiker-Kleiner D, Galuppo P, Bauersachs J
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(2020). miR-21, Mediator, and Potential Therapeutic Target in the Cardiorenal Syndrome. Front Pharmacol. 11:726
Huang CK, Bär C, Thum T
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miR-21 and NT-proBNP Correlate with Echocardiographic Parameters of Atrial Dysfunction and Predict Atrial Fibrillation. J Clin Med. 2020 Apr 14;9(4). pii: E1118
Sieweke JT, Pfeffer TJ, Biber S, Chatterjee S, Weissenborn K, Grosse GM, Hagemus J, Derda AA, Berliner D, Lichtinghagen R, Hilfiker-Kleiner D, Bauersachs J, Bär C, Thum T, Bavendiek U
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MiRNA-181a is a novel regulator of aldosterone-mineralocorticoid receptormediated cardiac remodelling. EurJ Heart Fail. 2020 Apr 18
Garg A, Foinquinos A, Jung M, Janssen-Peters H, Biss S, Bauersachs J, Gupta SK, Thum T
