Abstract
Common FADS2 haplotypes associated with hyperactivity of its gene product, delta-6-desaturase (D6D), predict cardiovascular morbidity and mortality in humans. D6D is the rate-limiting enzyme in essential polyunsaturated fatty acid (PUFA) metabolism, but its role in the pathogenesis of cardiovascular disease is unclear. To investigate this, we generated mice with global (CMV promoter) transgenic overexpression of FADS2 and evaluated their cardiometabolic phenotype. FADS2 -tg mice exhibit mild glucose intolerance and aortic stiffening with advancing age, but no overt cardiac pathology. However, when challenged with ischemia-reperfusion (I/R) ex vivo , FADS2 -tg mouse hearts have greater infarct sizes compared to their wild-type (WT; FVB) counterparts. Mitochondrial phospholipid analyses revealed a 65% increase in the membrane arachidonic/linoleic acid (AA/LA) ratio of FADS2- tg versus WT hearts, consistent with previous work in our lab linking D6D hyperactivity with mitochondrial phospholipid remodeling and disease progression in heart failure. Thus, we hypothesized that FADS2 might exacerbate myocardial injury by altering mitochondrial responses to ischemia-reperfusion. To examine this further, mitochondria were isolated from FADS2 -tg or WT mouse hearts for functional studies following 45/90 minutes of global I/R ex vivo . FADS2- tg - I/R mitochondria exhibited lower ADP-stimulated respiration and higher H 2 O 2 emission per O 2 consumed compared to WT-I/R and non-ischemic controls , suggesting impaired cardiac energetics and greater oxidant burden following ischemia. I/R augmented Ca 2+ -induced swelling in both WT and FADS2 -tg mitochondria. This was attenuated in the presence of K + in WT, but not FADS2 -tg, implicating FADS2 -dependent alterations post-ischemic in mitochondrial K + handling. Interestingly, ischemia led to a 38% depletion of mitochondrial membrane AA in FADS2 -tg, but not WT hearts, suggesting an interaction of FADS2 and mitochondrial membrane AA liberation following ischemia. Ongoing studies in our laboratory are investigating the potentially novel links between FADS2 expression with mitochondrial phospholipases, AA signaling, and mitoK ATP channel activity in the pathogenesis of myocardial I/R injury.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
