Endothelial derived, secreted long non-coding RNAs Gadlor1 and Gadlor2 aggravate cardiac remodeling

Merve Keles; Steve Grein; Natali Froese; Dagmar Wirth; Felix A Trogisch; Rhys Wardman; Shruthi Hemanna; Nina Weinzierl; Philipp-Sebastian Koch; Stefanie Uhlig; Santosh Lomada; Gesine M Dittrich; Malgorzata Szaroszyk; Ricarda Haustein; Jan Hegermann; Abel Martin-Garrido; Johann Bauersachs; Derk Frank; Norbert Frey; Karen Bieback; Julio Cordero; Gergana Dobreva; Thomas Wieland; Joerg Heineke

doi:10.1016/j.omtn.2024.102306

Endothelial derived, secreted long non-coding RNAs Gadlor1 and Gadlor2 aggravate cardiac remodeling

Mol Ther Nucleic Acids. 2024 Aug 15;35(3):102306. doi: 10.1016/j.omtn.2024.102306. eCollection 2024 Sep 10.

Authors

Merve Keles^{1

2

3}, Steve Grein^{1

3}, Natali Froese⁴, Dagmar Wirth⁵, Felix A Trogisch^{1

2

3}, Rhys Wardman^{1

3}, Shruthi Hemanna^{1

3}, Nina Weinzierl¹, Philipp-Sebastian Koch⁶, Stefanie Uhlig⁷, Santosh Lomada^{3

8}, Gesine M Dittrich^{1

3}, Malgorzata Szaroszyk⁴, Ricarda Haustein⁴, Jan Hegermann⁹, Abel Martin-Garrido¹, Johann Bauersachs⁴, Derk Frank^{10

11}, Norbert Frey^{3

12}, Karen Bieback⁷, Julio Cordero¹³, Gergana Dobreva^{3

13}, Thomas Wieland^{3

8}, Joerg Heineke^{1

2

3}

Affiliations

¹ ECAS (European Center for Angioscience), Department of Cardiovascular Physiology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany.
² CFPM (Core Facility Platform Mannheim), Cardiac Imaging Center, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany.
³ DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, 69120 Heidelberg, Germany.
⁴ Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany.
⁵ Helmholtz Center for Infection Research, Model Systems for Infection and Immunity, 38124 Braunschweig, Germany.
⁶ Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
⁷ CFPM, FlowCore, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany.
⁸ ECAS, Department of Experimental Pharmacology, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany.
⁹ Institute of Functional and Applied Anatomy, Core Unit Electron Microscopy, Hannover Medical School, 30625 Hannover, Germany.
¹⁰ Department of Internal Medicine III, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.
¹¹ DZHK, partner site Hamburg/Kiel/Lübeck, 20246 Hamburg, Germany.
¹² Department of Internal Medicine III, Medical Faculty Heidelberg, Heidelberg University, 69120 Heidelberg, Germany.
¹³ ECAS, Department of Cardiovascular Genomics and Epigenomics, Medical Faculty Mannheim of Heidelberg University, 68167 Mannheim, Germany.

Abstract

Pathological cardiac remodeling predisposes individuals to developing heart failure. Here, we investigated two co-regulated long non-coding RNAs (lncRNAs), termed Gadlor1 and Gadlor2, which are upregulated in failing hearts of patients and mice. Cardiac overexpression of Gadlor1 and Gadlor2 aggravated myocardial dysfunction and enhanced hypertrophic and fibrotic remodeling in mice exposed to pressure overload. Compound Gadlor1/2 knockout (KO) mice showed markedly reduced myocardial hypertrophy, fibrosis, and dysfunction, while exhibiting increased angiogenesis during short and prolonged periods of pressure overload. Paradoxically, Gadlor1/2 KO mice suffered from sudden death during prolonged overload, possibly due to cardiac arrhythmia. Gadlor1 and Gadlor2, which are mainly expressed in endothelial cells (ECs) in the heart, where they inhibit pro-angiogenic gene expression, are strongly secreted within extracellular vesicles (EVs). These EVs transfer Gadlor lncRNAs to cardiomyocytes, where they bind and activate calmodulin-dependent kinase II, and impact pro-hypertrophic gene expression and calcium homeostasis. Therefore, we reveal a crucial lncRNA-based mechanism of EC-cardiomyocyte crosstalk during heart failure, which could be specifically modified in the future for therapeutic purposes.

Keywords: MT:Non-coding RNAs; calcium/calmodulin-dependent protein kinase type II; cardiac angiogenesis; extracellular vesicles; heart failure; hypertrophy.