RUNX2-mediated pulmonary artery remodeling as a pathomechanism and therapeutic target in pulmonary hypertension due to left heart disease

• Applicants: Professor Dr. Christoph Knosalla; Dr. Mariya Kucherenko; Professor Dr. Wolfgang Kübler
• Subject Area: Cardiac and Vascular Surgery ; Anatomy and Physiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549161294

Pulmonary hypertension is a frequent complication in patients with left heart disease that contributes significantly to morbidity and mortality. Initially caused by retrograde congestion into the pulmonary circulation, pulmonary hypertension due to left heart disease (PH-LHD) can subsequently progress due to remodeling of pulmonary veins and arteries, and ultimately cause right ventricular dysfunction and failure. In spite of its high prevalence, the pathomechanisms of lung vascular remodeling in PH-LHD are little understood, and there are no approved clinical therapies for its treatment as of today. Vascular calcification, i.e. the deposition of calcium-phosphate complexes in the vascular wall, has recently emerged as critical pathomechanisms in systemic cardiovascular diseases and is typically driven by osteogenic transformation of smooth muscle cells mediated by activation of runt-related transcription factor-2 (RUNX2). In PH-LHD, prevalence, relevance and underlying mechanisms of vascular calcification have so far not been addressed; yet calcification-related stiffening of pulmonary arteries could be expected to drive the progression of PH-LHD via a mechanobiological feedback. Of late, we have identified such pulmonary arterial stiffening as important characteristic and propagator of PH-LHD. In preliminary work, we now demonstrate this effect to be associated with pulmonary arterial calcification and the upregulation of RUNX2 in PH-LHD patients and in a corresponding rat model of PH-LHD. Our pilot data further suggest a multifaceted regulation of RUNX2 by transcriptional, post-transcriptional and post-translational mechanisms in PH-LHD. In the present project, we thus propose a critical role for RUNX2 in lung vascular remodeling in PH-LHD. Specifically, we aim to (i) elucidate pulmonary vascular calcification and its association with pulmonary artery stiffness and pulmonary hemodynamics as a previously unrecognized pathomechanism in PH-LHD, (ii) to delineate the molecular mechanisms driving pulmonary vascular calcification in PH-LHD, (iii) to probe for non-osteogenic effects of RUNX2 on lung vascular remodeling, and (iv) to utilize this knowledge to target RUNX2-mediated pulmonary artery calcification and remodeling as therapeutic approach in PH-LHD. Successful realization of these aims is expected to i) reveal the relevance of pulmonary vascular calcification as a marker and pathomechanisms of lung vascular remodeling in PH-LHD, ii) advance our understanding of the role and regulation of RUNX2 in the pulmonary vasculature, and iii) identify novel strategies targeting vascular calcification and pulmonary artery stiffening as a treatment for PH-LHD. As such, we anticipate the proposed work to generate significant insight and impact for a common and severe disease which presently lacks therapeutic interventions.

• DFG Programme: Research Grants