The Role of SALTe1 in Vascular Aging and Heart Failure With Preserved Ejection Fraction

Summary / Abstract Heart Failure (HF) is a major cause of death in the United States. Advanced age is a major risk factor for HF and overall cardiovascular disease. HF with preserved ejection fraction (HFpEF) is the predominant form in older adults, accounting for more than 50% of HF cases. Effective treatment to improve outcomes is lacking, and prognosis remains poor for patients with HFpEF. Thus, there is a growing unmet clinical need for novel therapeutic approaches in HFpEF. Aging-associated decline in microvascular function is one of the major risk factors for HFpEF. However, a causal role has not been firmly established and little is known about the mechanisms regulating microvascular aging in HFpEF, and whether they can be effectively harnessed. Our previous studies showed that exercise training is effective in reversing cardiac aging phenotypes associated with HFpEF and restoring cardiomyogenesis in aged mice. We recently identified SALTe1 (Senescence Associated LncRNA Transcript in exercise 1), a long noncoding RNA (lncRNA) upregulated in the heart from aged mice and downregulated by exercise. Our preliminary studies found that (1) SALTe1 is conserved and highly expressed in endothelial cells. (2) In primary cardiac endothelial cells, SALTe1 overexpression induced cellular senescence and reduced angiogenesis, while its inhibition reduced senescence and improved angiogenesis. (3) In vivo in aged mice, systemic inhibition of SALTe1 reduced endothelial cell senescence and improved diastolic function. (4) SALTe1 regulates PARP9 and RBPMS. (5) SALTe1 is regulated by N6-methyladenosine. We hypothesize that SALTe1 is sufficient/necessary to induce microvascular aging, leading to HFpEF during aging. We will test this hypothesis in three specific aims: (1) to determine the role of SALTe1 in vascular aging, (2) to examine the role of SALTe1 in HFpEF, and (3) to examine the mechanisms by which SALTe1 regulates vascular aging. We anticipate that these studies will shed new lights into the role of lncRNAs (e.g., SALTe1) in the pathophysiology of microvascular aging and HFpEF. Moreover, these studies will establish clinically relevant approaches targeting SATLe1 to combat HFpEF in aging individuals. 1