Scientific Associate University Health Network, Ontario, Canada
Background: Heart failure (HF) is associated with abnormal cardiac metabolism, including diminished ATP production, and reduced substrate flexibility. However, the nature of this metabolic remodeling is complex, depending on the severity and type of HF, as well as co-morbidities such as obesity, type-2 diabetes and ischemia. We identified mitochondrial trifunctional protein(MTP), a key regulator of fatty-acid oxidation, as a mediator of the cardioprotective action of GLP-1(28-36), a naturally occurring metabolite of glucagon-like peptide-1(GLP-1). However, the role of MTP in metabolic remodeling associated with HF-subtypes remains largely unclear.
METHODS AND RESULTS: To study the expression, regulation and activity of cardiac MTP in HF, we subjected 10-12wk old C57BL/6 wild-type mice to permanent LAD ligation [myocardial infarction(MI)] and transverse aortic constriction (TAC) surgery to induce HF with reduced ejection fraction (HFrEF). Separately, we combined high-fat-diet (HFD; 60%-calories from fat) and nitric-oxide synthase inhibitor L-NAME (0.5g/l in drinking water) to generate metabolic and mechanical-stress induced ‘two-hit’ model of HF with preserved ejection fraction (HFpEF). High-resolution echocardiography was performed to analyze cardiac function at d-28 post-MI and 8-wk post-TAC to establish HFrEF, and global longitudinal strain was measured at 15-wk post-HDF+L-NAME to establish HFpEF. Hearts were isolated from mice with established HF to perform Western-blot analysis for MTPα- and MTPβ-subunit protein expression and NADH consumption-based kinetic assay to assess MTP enzyme activity.
We identified significantly reduced MTPα and MTPβ protein expression in post-MI HFrEF hearts vs. sham controls (P < 0.001, N=5/group). In contrast, no differences were found in MTP protein levels in post-TAC HFrEF (N=5/group). However, we observed increased cardiac MTPα protein levels (P < 0.001, N=5/group) and a trend towards increased MTPβ in post-HFD+L-NAME HFpEF hearts vs. regular chow controls. Consistent with MTP protein expression, we identified reduced MTPα activity in post-MI HFrEF hearts vs. sham controls (P < 0.001, N=5/group) with no changes observed in MTPα activity in post-TAC HFrEF. Finally, hearts from HFpEF mice showed increased MTPα activity vs. regular chow controls (P < 0.05, N=5/group). As such, MTPα activity parallels MTP protein levels in both models of HFrEF and HFpEF. Correlation plots between relative MTP expression levels and enzyme activities demonstrate strong positive correlation in post-MI HFrEF (r=0.71) and post-HFD+L-NAME HFpEF (r=0.92).
Conclusion: MTP expression and enzyme activities are differentially regulated in distinct mouse models of HF. Further studies are needed to determine whether these alterations are the cause or consequence of metabolic remodeling in these HF-subtypes, potentially implicating MTP as a critical mediator and therapeutic target.
