Synergism between obesity and HFpEF on neutrophils phenotype and its regulation by adipose tissue‐molecules and SGLT2i dapagliflozin

Abstract

The adiposity invokes innate immune activity, coronary microvascular dysfunction and consequently heart failure preserved ejection fraction (HFpEF). Our aim was to study the neutrophils profile on obesity and cardiovascular disease and its regulation by adipose tissue‐secretome and dapagliflozin. We have isolated neutrophils from patients undergoing open heart surgery (19 women and 51 men). Its migration activity was performed with culture‐transwell, transcriptional studies of proteolytic enzymes, adhesion molecules or receptors were analysed by real‐time PCR and proteomics (from 20 patients) analysis by TripleTOF mass spectrometer. Differentiated HL‐60 (dHL‐60) was used as a preclinical model on microfluidic for endothelial cells attaching assays and genes regulation with epicardial and subcutaneous fat secretomes from patients (3 women and 9 men) or dapagliflozin 1–10 μM treatments. The transcriptional and proteomics studies have determined higher levels of adhesion molecules in neutrophils from patients with obesity. The adhesion molecule CD11b levels were higher in those patients with the combined obesity and HFpEF factors (1.70 ± 0.06 a.u. without obesity, 1.72 ± 0.04 a.u. obesity or HFpEF without obesity and 1.79 ± 0.08 a.u. obesity and HFpEF; p < .01). While fat‐secretome induces its upregulation, dapagliflozin can modulated it. Because CD11b upregulation is associated with higher neutrophils migration and adhesion into endothelial cells, dapagliflozin might modulate this mechanism on patients with obesity and HFpEF.

Semaglutide modulates prothrombotic and atherosclerotic mechanisms, associated with epicardial fat, neutrophils and endothelial cells network

“…Consequently, less insulin resistance suggested a reduction of lipolysis and circulating FABP4 levels in patients after 6 months treatment. Previous data had demonstrated a higher CD11b mRNA expression levels in neutrophils from patients with obesity and CVD and subcutaneous fat-released molecules might be possible mediators [ 8 ]. In our population, high neutrophils-CD11b was positively associated with plasma insulin levels (r = 0.5; p < 0.05) which are related to adipose tissue resistance.…”

“…The crosstalk between adipocytes and neutrophils [ 4 ], which are increased [ 5 ]and infiltrated into adipose tissue [ 6 ] participates in this pathological condition. The released molecules by adipose tissue, named adipokines, are also good players on neutrophilia [ 7 ] and phenotypic changes of neutrophils [ 8 ], based on proteins of cell membrane and enzymes that accelerate their adhesion over endothelial cells [ 9 ] or IR in adipocytes [ 10 ], respectively. Chronic inflammation in obesity is related to higher neutrophils infiltration on adipose tissue, through interaction between neutrophils-CD11b and adipocytes-intercellular adhesion molecule 1 (ICAM-1) [ 6 ] that precede macrophages infiltration.…”

“…Our previous results have also demonstrated higher CD11b expression levels on circulating neutrophils in patients with CVD and obesity than those without obesity. In fact, it was accentuated in patients with HFpEF [ 8 ],and coronary artery disease (CAD) is one of its significant risk factors [ 11 ]. Atherogenesis is one of the involved mechanisms where the role of neutrophils was underestimated due to their short life span or their phenotypic plasticity.…”

Personalized Management for Heart Failure with Preserved Ejection Fraction

“…Accordingly, HFpEF can be classified into different phenotypes based on various criteria, including underlying etiology, clinical characteristics, and comorbidities [ 3 , 4 , 5 , 6 , 7 , 8 ]. Detailed molecular signaling, gene ontology functional analysis, and the use of the Kyoto Encyclopedia of Genes and Genomes pathway also potentiate the precise mechanisms of action and targets of SGLT2 inhibitors in clinical practice [ 9 , 10 ]. A comprehensive understanding and the specific pathways identified from HFpEF phenotyping also facilitate animal experimental studies to address relevant pathophysiological signaling [ 11 ].…”

Epicardial Adipose Tissue in Obese Heart Failure With Preserved Ejection Fraction

“… 13 Sodium-glucose co-transporter 2 inhibitors and statins may potentially ameliorate inflammation in EAT. 16 , 17 Surgical or minimally invasive pericardiotomy may be effective in reducing pericardial restraint in patients with obese HFpEF. 18 …”