FADS2 Overexpression Increases Cardiovascular Risk and Ischemic Injury in Mice
Authors: LiPuma Lance C , Whitaker Connor M , Olson Adrian J , Evans Amanda J , Mulligan Christopher M , Le Catherine H , Chicco Adam J 
Published: November 2023

Alterations in the polyunsaturated fatty acid (PUFA) composition of myocardial phospholipids have been reported in various forms of cardiac pathology for over 25 years. The pattern of PUFA redistribution is remarkably consistent across diverse etiologies and experimental models, manifesting primarily as a proportional loss of the essential PUFA linoleic acid (LA) paralleled by reciprocal increases in long‐chain highly unsaturated arachidonic (AA) and/or docosahexaenoic acids (DHA). Epidemiological studies have linked a similar pattern in serum phospholipids to elevated cardiometabolic risk and single nucleotide polymorphisms in the FADS2 gene encoding delta‐6 desaturase, the rate‐limiting enzyme in the conversion of essential PUFAs into AA and DHA. To determine if FADS2 was capable of promoting tissue phospholipid PUFA remodeling and a pathogenic cardiac phenotype in the absence of preexisting disease, we generated mice with global transgenic overexpression of FADS2 and evaluated their cardiac phenotype across 8 backcrossed (FVB) generations. FADS2‐tg mice exhibit moderate elevation of D6D protein expression in liver compared to wild‐type FVB (WT) mice, but nearly undetectable levels in heart from both genotypes. Despite this, hearts from FADS2‐tg mice exhibit significant elevations in phospholipid D6D product/precursor PUFA ratios (e.g., AA/LA), which parallel similar patterns in serum, liver and muscle. Compared to WT, FADS2‐tg mice develop significantly greater left ventricular end‐diastolic and end‐systolic dimensions by echocardiography at 2–4 months of age (27% and 93%, respectively), which results in a moderate (23%), but significant decrease in fractional shortening (P < 0.01). This is associated with greater levels of phosphorylated extracellular regulated kinase 1/2 expression and the pro‐hypertrophic AA‐derived eicosanoid 12‐hydroxyeicosatetraenoic acid, but no gross changes in tissue morphology or fibrosis. This phenotype does not appear to progress with age, but FADS2‐tg mice also develop moderate hyperlipidemia, glucose intolerance, and early mortality compared to WT, suggesting a more complex cardio‐metabolic phenotype. To evaluate the tolerance of FADS2‐tg hearts to pathogenic metabolic stress, hearts were isolated and Langendorff perfused for a 45/120 min protocol of global ischemia/reperfusion ex vivo, followed by assessment of myocardial infarct size by conventional triphenyltetrazolium chloride staining. Interestingly, preliminary results indicate that FADS2‐tg hearts exhibit ~15% greater infarcts following I/R compared to WT (P < 0.05; N = 4–5/group). Taken together, these studies implicate FADS2 and perhaps tissue phospholipid PUFA composition as important modulators of cardiovascular risk, consistent with epidemiological evidence from FADS2 haplotypes and serum PUFA profiling studies in humans. The possible mechanisms underlying this link are currently being explored in FADS2‐tg mice and other genetic models in our laboratory.

Support or Funding Information

These studies were supported by grants from the NHLBI and the American Heart Association to AJC.