Failure of Right Ventricular Adaptation to Pressure Overload Due to a Profound Deficiency in Adenylate Kinase 1 and Impaired Ventricular Energetics
CIRCULATION(2021)
Abstract
Introduction: Interindividual heterogeneity in the ability of the right ventricular (RV) to adapt to pressure overload in pulmonary hypertension (PH) is likely influenced by genetic determinants. We took advantage of strain-dependent, maladaptive RV remodeling in Fischer compared to Sprague-Dawley (SD) rats to define the molecular and genetic mechanisms that predispose to development of RV failure in PH. Methods/Results: In the SU5416/hypoxia(SUHx) PH model, Fischer rats exhibited RV failure and 100% mortality by 5-weeks, whereas SD rats showed preserved RV function and 88% survival beyond 9 weeks (p<0.0001). In vivo oxidative metabolism, assessed by [ 11 C]acetate PET, was increased in Fischer rats at 4 weeks (p<0.05), associated with impaired RV efficiency compared to SD (work metabolic index: 58±12 vs 102±20 mmHg·mL/cm 2 , respectively; p<0.001), but no differences were observed in mitochondrial complex activity in permeabilized RV cardiac fibers. Adenylate Kinase 1 (AK1) was among the top ten differentially expressed genes between Fischer and SD rats by unbiased transcriptomic analysis, with markedly lower expression in the RV of Fischer rats (FC:3.36, P<0.05). Profound AK1 deficiency was confirmed by proteomics and validated by Western blotting (>10-fold reduction, P<0.001). Fischer rats also exhibited evidence of hemolysis, recapitulating the hemolytic phenotype seen in patients with rare AK1 coding region mutations. While whole genome sequencing failed to reveal any coding region mutations in Fischer rats, there was a unique variant in a highly conserved upstream flanking region. AK1 levels were also reduced in the RV of PH patients with decompensated RV function and right heart failure. Conclusion: Fischer rats with AK1 deficiency have inefficient energetics likely related to reduced ATP shuttling from the mitochondria to the contractile fibers, which represents a novel mechanism for RV failure in response to chronic increases in afterload.
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Key words
adenylate kinase,right ventricular adaptation,pressure overload
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