The role of the z-disc protein LMCD1 in cardiac remodeling.

• Applicant: Professor Dr. Derk Frank
• Subject Area: Cardiology, Angiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467267736

Cardiovascular diseases are the leading cause of death worldwide. One major contributor to unhealthy changes-in the heart muscle is long-term pressure overload - often caused by untreated high blood pressure or a narrowed (stenotic) aortic valve. This chronic stress forces the heart to adapt by thickening its walls (hypertrophy). While this may help in the short term, over time it leads to harmful remodeling: the heart becomes stiff, forms scar tissue (fibrosis), loses its pumping power, and eventually develops heart failure. This research project focuses on a specific protein called LMCD1, found in a structural region of heart muscle cells known as the Z-disc. Early findings suggest LMCD1 plays a damaging role in the progression of cardiac remodeling. In previous DFG-funded studies, mice with significantly reduced LMCD1 levels in the heart showed better outcomes under pressure overload. These mice had smaller hearts, less fibrosis, and preserved heart function. The aim of this new project is to explore whether LMCD1 can also be targeted therapeutically - not just preventively. In other words, can reducing LMCD1 after heart disease has already begun slow down or even reverse the damage? To test this, researchers will use specially designed microRNAs to silence the LMCD1 gene. These small RNA molecules are delivered directly into heart cells using AAV vectors - a method already used in human gene therapy. The study will examine whether this LMCD1 knockdown can counteract disease progression caused by the hormone angiotensin II in mice, which mimics the changes caused by high blood pressure. Both male and female mice will be included to identify any sex-specific responses. Beyond the therapeutic potential, the project also aims to uncover the detailed molecular role of LMCD1: How does it influence metabolism in heart cells? Which other proteins does it interact with? What signaling pathways does it activate or suppress? To answer these questions, the team will use a range of modern tools such as RNA sequencing, proteomics, and cell models derived from both rats and human stem cells. This research is not only valuable for advancing basic science but may also pave the way for new treatment strategies against heart failure. The project is designed with ethical and sustainable research practices in mind - minimizing animal use, following the 3R principles (Replace, Reduce, Refine), and planning experiments to conserve resources. Ultimately, the goal is to better understand and potentially treat pathological left ventricular thickening (hypertrophy) - a key driver of chronic heart failure.

• DFG Programme: Research Grants