Right Ventricular Maladaptation to Pressure Overload in Fischer Rats Is Associated With Profound Deficiency in Adenylate Kinase 1 and Impaired Ventricular Energetics

Abstract

BACKGROUND: We explored the mechanism of maladaptive right ventricular (RV) remodeling in Fischer compared with Sprague-Dawley (SD) rats exposed to pressure overload. METHODS: Pulmonary hypertension was induced by injection of the VEGFR antagonist, SU5416, followed by a 3-week exposure to hypoxia (Sugen chronic hypoxia). In vivo oxidative metabolism was assessed by RV/left ventricle ratio of [ 11 C]acetate positron emission tomography clearance (kmono). Unbiased, global transcriptional and proteomic profiling was performed in Fischer and SD rats at baseline and after Sugen chronic hypoxia. RESULTS: All Fischer rats succumbed to RV failure by 5 weeks, whereas SD rats showed preserved RV function and 88% survival beyond 9 weeks ( P <0.0001). Fischer rats exhibited increased oxidative metabolism at 4 weeks ( P <0.05) and impaired RV efficiency compared with SD (work metabolic index: 52±10 versus 91±27 mmHg·mL/cm 2 , respectively; P <0.05), but no differences in mitochondrial complex activity. AK1 (adenylate kinase 1) was among the top 10 differentially expressed genes between Fischer and SD rats, with markedly lower RV expression in Fischer rats (FC: 3.36, P <0.05), confirmed by proteomic analysis and validated by Western blotting (>10-fold reduction, P <0.001). 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 likely involved in the regulation of AK1 expression. CONCLUSIONS: Therefore, Fischer rats exhibit profound AK1 deficiency and inefficient cardiac energetics likely related to reduced adenosine triphosphate shuttling from the mitochondria to the contractile fibers. This represents a novel mechanism for RV failure in response to chronic increases in afterload.

Identification and analysis of co-disease genes between COVID-19 and osteoarthritis

“…We found the hub gene of osteoarthritis and COVID-19 through bioinformatics methods, and screened seven biomarkers, AK1, APP, ENO1, TPI1, HSP90B1, HSPB1 and ESR1. Adenylate kinase 1 (AK1) is an enzyme in the AK family that catalyzes nucleotide phosphorylation and regulates intracellular ATP concentration [21] . AK transfers the phosphate group at the end of ATP to AMP, forming two ADP molecules that participate in nucleic acid synthesis and cell energy metabolism, and play an important role in regulating tumor cell metabolism, cell migration, and invasion [22] .…”

Right ventricular diastolic adaptation to pressure overload in different rat strains

“…Shults et al, showed that Fischer344 rats developed pulmonary vascular and RV remodeling faster, but the degree of RV pressure elevation and extent of RV fibrosis were similar to Sprague Dawley rats. Fischer344 rats seem to lack the capability of adapting and repairing RV damage and show signs of inefficient cardiac energetics (Lee et al., 2020; Zelt et al., 2022). Genetic factors have been emphasized as important contributors to the susceptibility of PH (Shults et al., 2019; Suen et al., 2019).…”

Rodent Models of Dilated Cardiomyopathy and Heart Failure for Translational Investigations and Therapeutic Discovery

“…Interbreed differences exist in the RV response to the sugen/hypoxia pulmonary hypertension model. Fisher rats display an early maladaptive RV remodeling leading to exitus by 5 weeks, while Sprague Dawley rats can show preserved RV performance and survival even beyond 9 weeks [ 86 ]. Proteomics analysis revealed that a significant downregulation of adenylate kinase 1 (ADK1), which translates into inefficient cardiac energetics, might be the molecular substrate for the premature deterioration of RV function in Fisher rats [ 86 ].…”

“…Fisher rats display an early maladaptive RV remodeling leading to exitus by 5 weeks, while Sprague Dawley rats can show preserved RV performance and survival even beyond 9 weeks [ 86 ]. Proteomics analysis revealed that a significant downregulation of adenylate kinase 1 (ADK1), which translates into inefficient cardiac energetics, might be the molecular substrate for the premature deterioration of RV function in Fisher rats [ 86 ]. In Sprague Dawley rats, RV hypertrophy and increased filling pressures are present after 5 weeks, with a subsequent RV enlargement by 8 weeks, but still preserved RV stroke volume and ejection fraction [ 85 ].…”