In this study, we aimed to investigate the serum FAs in pressure-induced HF mice with eWAT reserved and eWAT excised. Mice without aortic constriction that underwent a similar surgical procedure served as controls. We demonstrated for the first time that from among multitudinous serum FAs, arachidic acid, behenic acid, lignoceric acid, and docosapentaenoic acid levels were significantly decreased in pressure-induced cardiac failure model. In addition, removal of eWAT significantly alleviated cardiac structure and function in HF mice accompanied by a decrease in these four serum FAs levels, indicating non-cardiac tissues such as eWAT participate in the regulation of cardiac failure.
The role of WAT in HF development and cardiac metabolism has been previously studied, with most studies focusing mainly on cardiac lipase function [14, 15]. In this study, we concentrated on VAT and the impact of adipose tissue lipolysis on the development of pressure-induced cardiac failure. This study revealed that the serum triacylglycerol (TG) level was significantly increased in pressure-induced HF mice compared to controls. Our findings corroborated previous studies that reported a positive association between increased adipose tissue lipolysis and impairment of cardiac function in heart failure models [16, 17]. Circulating FAs are liberated from WAT via hydrolysis of TG which is catalyzed by two major adipose tissue lipases, hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), under hormonal control [18]. Deletion of ATGL in adipose tissue prevents pressure-induced LV failure by decreasing adipose tissue lipolysis [19]. Consistent with previous studies, our findings showed that removal of eWAT significantly alleviated pressure-induced cardiac hypertrophy and fibrosis, as evidenced by decreased mRNA expression of cardiac hypertrophy and fibrosis genes ANP, COL1, and COL3A1.
Fatty acids are involved in post-translational modification of proteins through protein acylation and activation of protein kinases. Recent experimental findings have indicated that several cardiac genes are under the control of fatty acids [20, 21]. However, there are multiple FAs present in circulating bloodstream, and it is not clear which of them are mainly involved in cardiac energy metabolism. We analyzed serum FAs using HPLC, which was previously utilized in cardiovascular research for the identification of new molecular co-mediator of exercise-induced cardiac hypertrophy [13]. Our study found that serum arachidic acid, behenic acid, lignoceric acid, and docosapentaenoic acid levels were significantly decreased in pressure-induced cardiac injury. Arachidic acid, behenic acid, and lignoceric acid are long-chain saturated FAs that are found in circulation. Circulating long-chain saturated FAs with 20 carbons or more are integrated biomarkers of diet and metabolism [22]. The long-chain saturated FAs are known components of ceramides that are involved in apoptosis and cardiac dysfunction [23, 24]. The heart of genetically engineered mice with reduced ceramides containing long-chain saturated FAs showed increased fibrosis, endoplasmic reticulum stress, and apoptosis [25]. Lemaitre et al have identified an association of higher levels of plasma phospholipid very-long-chain saturated fatty acids with lower risk of incident HF in a prospective cohort of older American adults [22]. Similar results were obtained in our study, indicating that decreased arachidic acid, behenic acid, and lignoceric acid were probably involved in pressure-induced cardiac failure. In addition, we also found that the serum level of docosapentaenoic acid, a long-chain unsaturated fatty acid, was significantly decreased in pressure-induced HF mice. In addition, we found no increased levels of FAs in serum of pressure-induced heart failure mice. This eliminated the probability that these reduced fatty acids were converted to other fatty acids. Thus, we hypothesized that these four fatty acids are involved in cardiac function impairment during pressure overload. However, this needs to be verified by analyzing lipid class in cardiac tissue through further studies.
The current study found that mice after removal of eWAT showed a marked reduction of these four fatty acids in both normal and pressure-induced HF mice compared to mice with eWAT reserved, which indicated that these four fatty acids may be principally derived from eWAT. In addition, we observed a slightly, but not significantly, decreased TG and FFA levels. eWAT serves as a main VAT, which can more easily produce FFA than subcutaneous adipose tissue (SAT) because VAT has higher expression of adrenergic receptors 1, 2, and 3 on the cell membrane [26, 27]. Surprisingly, no significant differences were found in circulating FFA and TG after eWAT removal in this study. One possible explanation for this might be that VST is mainly distributed around abdominal organs including epididymal adipose tissue, omental adipose tissue, mesenteric adipose tissue, retroperitoneal adipose tissue, perirenal adipose tissue, etc [28]. Although eWAT was removed in this study, other visceral adipose tissues may have also played a role in producing FFA. Another possible explanation might be because of the difference in the experimental period selected in this study. There are, however, other possible explanations that need to be further studied. The mechanisms underlying the differential impact of adipose tissue on cardiometabolic risk have started to be unraveled; the inability of the subcutaneous adipose tissue to expand in response to positive energy balance serves as an important mechanism that necessitates further studies on the subcutaneous adipose tissue.