Shared and Distinct Cellular and Molecular Landscapes of Cardiac Left Ventricle Injury in Three Models of Hypertension: Insights from Single-nucleus RNA Sequencing

Abstract

High blood pressure is the leading risk factor of heart diseases, affecting millions of patients who remain hypertensive despite taking three or more anti-hypertensive medications. Understanding the cellular and molecular basis of heart damage at cell type-specific level in different types of hypertension is crucial for developing targeted therapies. In this study, we applied 10x Genomics' single-nucleus RNA sequencing (snRNA-seq) technology to cardiac left ventricle samples from three well-established hypertension models: C57BL/6 mice treated with Ang II, the Dahl salt-sensitive rat, and the spontaneous hypertensive rat, along with their respective controls. Our dataset included 166,489 nuclei from 18 samples across 9 experimental conditions. Our analysis revealed a shared set of cellular and molecular changes across these hypertensive models. For instance, we observed extracellular matrix remodeling in fibroblasts in salt-sensitive and spontaneous hypertension, as indicated by increased collagen production. Endothelial cells showed an increased proportion in all three models, and showed higher levels of injury based on expression patterns of increased proliferation and migration. Both AngII-induced and spontaneous hypertension showed cardiomyocyte dysfunction, affecting cardiac muscle contraction and ATP metabolic process. Notably, impaired ATP generation was a common response in AngII-induced hypertension, involving not only cardiomyocytes but also endothelial cells and fibroblasts. During the progression of salt-sensitive hypertension, a notable increase in inflammation occurred, marked by steadily increasing immune cell infiltration, eventually reaching a 1.5-fold increase in immune cells. T cells were particularly elevated during the high-salt diet and actively engaged in the CD45 signaling network in the late stage of spontaneous hypertension, where an elevated interaction between cardiomyocyte and endothelial cells through vascular endothelial growth factor was observed. In conclusion, the utilization of snRNA-seq identified shared and distinct cellular and molecular changes associated with left ventricular injury in various models of hypertension. NIH grant HL149620. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.