Pharmacological Targeting of Senescence with ABT-263 in Experimental Heart Failure with Preserved Ejection Fraction

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fundação Ciência e Tecnlogia HFpEF is the most common form of heart disease in the elderly and is associated with high morbidity and mortality. Our understanding of HFpEF pathophysiology is limited and development of efficient therapies that alter the clinical course of the disease has proved greatly challenging. Although aging is a risk factor of HFpEF1, the involvement of aging hallmarks such as cell senescent and immunosenescence is unclear. Recently, a link between endothelial senescence and HFpEF development was demonstrated in mice with accelerated aging [1], endorsing anti-aging pharmacologic as potential new therapeutic alternatives for HFpEF. In fact, the senolytic (drugs that selectively promote apoptosis of senescent cells) ABT-263 has already proven efficacy in the context of cardiovascular diseases. Further studies are needed to clarify the relevance of aging and of anti-aging therapies in the context of HFpEF. Using ZSF1 obese rats (ZSF1-Ob) as model of HFpEF we showed from 18 weeks signs of immunosenescence compared to ZSF1-Ln, namely an increased frequency of circulating myeloid cells and decreased frequency of T and B cells. Concomitantly, expression of pro-inflammatory factors (IL-6, IL-1, TGF-β, TNF-α) was upregulated in peripheral blood mononuclear cells (PBMCs) of ZSF1-Ob which also displayed characteristic features of cell senescence (p21 expression, lysosomal endogenous Beta-galactosidase (SA-B-Gal) senescence-associated secretory phenotype (SASP) and up-regulation of BCL-XL. Importantly, no signs of cellular senescence (SA-B-gal, pH2AX and senescence associated pathways) were found in the main hematopoietic organs (spleen and bone marrow). Alongside, these systemic alterations, an upsurge of cellular senescence was observed in myocardium of ZSF1-Ob rats, particularly in endothelial and hematopoietic cells. Serum of ZSF1-Ob rat was able to induce activation and cellular senescence of cardiac microvascular endothelial cells, indicating that systemic circulating factors may be the upstream mechanism of cellular senescence and dysfunction in HFpEF. Analysis of HFpEF patients and a control cohort adjusted to main co-morbidities further demonstrated accumulation of senescent monocytes in HFpEF patients. In these patients, the senescence marker SA-B-Gal correlated with plasmatic brain natriuretic peptide (BNP) levels and pulmonary artery systolic pressure. Targeting aging hallmarks through the treatment of ZSF1-Ob rat with ABT-263 resulted in a reduction in circulating senescent cells, decreased systemic and local inflammation, re-established immune proportions, restore the levels of circulating BNP and attenuated myocardial remodeling, particularly endothelial dysfunction and fibrosis. Collectively these findings support that premature cellular senescence contributes to the establishment of a deleterious pro-inflammatory environment in HFpEF and that senolytic agents hold promise for the treatment of this syndrome.