Extrinsic and intrinsic modulators of inflammation-resolution signaling in heart failure

Abstract

Chronic and uncleared inflammation is the root cause of various cardiovascular diseases. Fundamentally, acute inflammation is supportive when overlapping with safe clearance of inflammation termed resolution; however, if the lifestyle-directed extrinsic factors such as diet, sleep, exercise, or physical activity are misaligned, that results in unresolved inflammation. Although genetics play a critical role in cardiovascular health, four extrinsic risk factors-unhealthy processed diet, sleep disruption or fragmentation, sedentary lifestyle, thereby, subsequent stress-have been identified as heterogeneous and polygenic triggers of heart failure (HF), which can result in several complications with indications of chronic inflammation. Extrinsic risk factors directly impact endogenous intrinsic factors, such as using fatty acids by immune-responsive enzymes [lipoxygenases (LOXs)/cyclooxygenases (COXs)/cytochromes-P450 (CYP450)] to form resolution mediators that activate specific resolution receptors. Thus, the balance of extrinsic factors such as diet, sleep, and physical activity feed-forward the coordination of intrinsic factors such as fatty acids-enzymes-bioactive lipid receptors that modulates the immune defense, metabolic health, inflammation-resolution signaling, and cardiac health. Future research on lifestyle- and aging-associated molecular patterns is warranted in the context of intrinsic and extrinsic factors, immune fitness, inflammation-resolution signaling, and cardiac health.

Keywords: chronic inflammation; heart failure; inflammation-resolution signaling; intrinsic-extrinsic factors; lifestyle-associated molecular patterns.

Figure 1.

At homeostatic and allostatic level, lifestyle factors such as diet, sleep, and physical activity/exercise are prime contributors to the health-disease path, including cardiac health. Unhealthy lifestyle factors, including unhealthy diet, sleep deprivation, and sedentary work culture, contribute to cardiometabolic and cardiovascular disease. An unhealthy lifestyle directly impacts hormones, diet/fat intake, metabolic enzymes, and obvious bioactive lipid mediators, thereby action on receptors. Extrinsic factors such as diet, sleep, and exercise profoundly impact intrinsic factors that modulate the immune defense activated due to pathogen, damage, lifestyle, and aging-associated molecular patterns. Fatty acids, such as arachidonic acid (AA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and docosapentaenoic acid (DPA), are used by lipoxygenase (LOX), cyclooxygenase (COX), and cytochrome-P450 (CYP) to form a variety of lipid mediators such as specialized proresolving lipid mediators (SPMs) and epoxyeicosatrienoic acids (EETs). AAMPs, aging-associated molecular patterns; DAMPs, damage-associated molecular pattern; LAMPs, lifestyle-associated molecular pattern; PAMPs, pathogen-associated molecular pattern.

Figure 2.

At organ level, arachidonate 5 lipoxygenase (ALOX5) and biosynthesis of specialized proresolving lipid mediators (SPMs) in cardiac repair following cardiac injury. In the presence of ALOX5, arachidonic acid (AA) metabolizes to leukotrienes (LTB₄) and lipoxins (LXA₄), whereas docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) convert to specialized proresolving mediators: D-series resolvin (Rv)-1,6 and maresin (MaR)-1,2 and EPA into E-series RvE1 that ultimately lead to high survival and resolution of inflammation heart failure (HF). In the absence of ALOX5 and aging, AA gets metabolized to prostaglandins (PGs) and other proinflammatory mediators (PIMs), leading to unresolved inflammation and cardiac impairment, leading to low survival in mice. Hematoxylin and eosin (H&E) images depicting heart structure in control and HF left ventricle in mouse model with/without coronary ligation. Images created with a licensed version of BioRender.com.

Figure 3.

At cellular level, macrophage centric role of 12/15-lipoxygenase (12/15-LOX) in the resolution of inflammation. In mice, deficiency of 12/15-LOX biosynthesizes 11,12- and 14,15-epoxyeicosatrienoic acid (EET) facilitates the safe clearance of inflammation, cardiac repair, and improved survival post-myocardial infarction (MI) as a compensatory mechanism. Supplementing a linoleic acid-rich diet to 12/15-LOX mice leads to the biosynthesis of EET and dihydroxy-9Z-octadecenoic acids (DiHOMEs) with resolving macrophage phenotypes post-MI. However, aging 12/15-LOX-null mice develop signs of suboptimal inflammation via biosynthesizing prostaglandins (PGs). 12-HETE, 12-hydroxyeicosatetraenoic acid; 15-HETE, 15-hydroxyeicosatetraenoic acid; AA, arachidonic acid; LA, linoleic acid-rich; PUFA, polyunsaturated fatty acids.

Figure 4.

At molecular level, specific specialized proresolving lipid mediators (SPMs) activate specific proresolution receptors for biological function in cardiac health. The formyl peptide receptor 2 (FPR2) mediates its effects via lipoxin A₄ (LXA₄). Resolvin D1 (RvD1) mediates its effect through G protein-coupled receptors (GPCRs): FPR2 and GPR32. RvD2 interacts with G protein receptor 18 (GPR18), whereas resolving E1 (RvE1) mediates its effect by Chem23 (chemokine-like receptor 1). Apart from SPMs, epoxyeicosatrienoic acids (EETs), i.e., 11,12-EET/14,15-EET, mediates their effect through the EP4 receptor. These mediators control the kinetics of leukocytes, as specified. Images created with a licensed version of BioRender.com.

Figure 5.

Role of primary and secondary triggers that influences cardiac health at wholistic level. Sleep, diet, and exercise/physical activity are the primary factors influencing secondary factors such as body mass index (BMI), blood pressure, blood glucose, and lipid profile. The imbalance of primary factors has feed-forward impact on secondary symptoms of disease such as high body mass, glucose, lipid, or blood pressure that are critical for cardiac health and disease. Furthermore, an imbalance of primary factors, along with the use of tertiary factors such as smoking, alcohol, comedications, and substance of abuse, triggers cardiac disease.