Abstract Body: Heart failure (HF), a global health challenge, arises when the heart fails to pump sufficient blood. HF is classified by left ventricular ejection fraction (LVEF): HF with preserved EF (HFpEF, EF ≥ 50%), reduced EF (HFrEF, EF ≤ 40%), and mildly reduced EF (HFmrEF, EF 40-50%). While HFrEF and HFmrEF share clinical characteristics, HFpEF differs markedly, with limited understanding and therapeutic options.
Prior work has suggested that endothelial dysfunction may be operative in HFpEF but mechanistic insights remain limited. We hypothesized that KLF4, a critical endothelial homeostasis, may impact the development of experimental HFpEF. We observed reduced KLF4 levels (mRNA and protein) in the cardiac endothelial cells (ECs) in experimental HFpEF. Endothelial transgenic mice overexpressing KLF4 were protected from HFpEF as evidenced by improved echocardiographic parameters (lower E/E’), improved coronary flow reserve, enhanced exercise tolerance, and reduced cardiac steatosis and fibrosis. By contrast, endothelial loss of KLF4 rendered animals susceptible to an exaggerated form of HFpEF.
Spatial single-cell RNA sequencing provided valuable insights into transcriptional regulation, addressing knowledge gaps in endothelial dysfunction's role in HFpEF. These findings underscore the importance of the endothelium in HFpEF pathophysiology and identify KLF4 as a critical target for therapeutic gain.