ABSTRACT
Heart failure (HF) is a leading cause of morbidity and mortality in the US and its prevalence is expected to rise
with the aging of the general population. Myocardial infarction (MI), chronic cardiac overload or valvular diseases
often lead to the loss of cardiomyocytes (CMs). However, the limited endogenous proliferation capacity of adult
CM impedes CM renewal and contributes to the development of HF. Interestingly, recent studies indicate that
hypoxia promotes CM proliferation and improves recovery after myocardial injury, suggesting that endogenous
pathways involved in CM proliferation can be activated and are sufficient to induce CM renewal without genetic
manipulation in both healthy and diseased hearts. Therefore, promotion of endogenous CM renewal is a
promising therapeutic approach to treat HF. However, the mechanisms involved in hypoxia-induced CM
proliferation remain largely unknown. Prolyl hydroxylase domain proteins (PHDs) are widely considered as the
oxygen sensors. Whether PHDs are involved in hypoxia-induced CM proliferation and renewal is unknown. Further,
endothelial cells (ECs) act as the “first-responder” to environmental cues such as oxygen and nutrients. It is
unclear whether cardiac EC-CM communication plays a role in hypoxia-induced CM proliferation. Therefore,
exploring the role of endothelial PHDs in CM proliferation is of critical importance for understanding the basic
mechanisms involved in endogenous CM renewal and will provide us novel approaches to treat HF.
We have recently demonstrated that EC-specific knockout (eKO) of PHD2/3 promoted CM proliferation,
improved cardiac function, and prevented ventricular failure induced by MI. Mechanistically, we discovered that
yes-associated protein (YAP), a key player of organ size control and CM proliferation, was specifically activated
in CMs of PHD2/3 eKO mice. Single-cell RNA sequencing (scRNA-seq) analysis revealed that apelin (Apln), a
GPCR ligand, was markedly upregulated in cardiac ECs of PHD2/3 eKO mice via HIF-2a. We further
demonstrated that Apln potently activated YAP in CMs and promoted CM proliferation. Notably, deletion of HIF-
2a or Apln in ECs eliminated the beneficial effects on cardiac function observed in PHD2/3 eKO mice. More
importantly, CM-specific deletion of Apln receptor (AplnR) in mice at neonatal or adult stages inhibited YAP
activation and deteriorated heart function. These data lead us to hypothesize that an endothelial PHD-mediated
paracrine mechanism plays a key role in CM proliferation and renewal via Apln/AplnR pathway. To test this
hypothesis, we will elucidate the underlying molecular mechanism by which endothelial PHD-mediated paracrine
pathways regulate Hippo-YAP signaling in CMs. In addition, we will study the essential role of Apln/AplnR
pathway in CM proliferation and normal heart function. Last, we will investigate the role of Apln/AplnR pathway
in mouse models of heart failure.