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Cavβ2a TG mice treated with hight fat diet and L‐Name is a model for HFpEF
Author(s) -
Li Yijia,
Zhang Xiaoying,
Jin Jianguo,
Molkentin Jeffery,
Houser Steven,
Chen Xiongwen
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.01898
Subject(s) - phospholamban , medicine , diastole , endocrinology , heart failure , contraction (grammar) , serca , myocyte , heart failure with preserved ejection fraction , cardiac function curve , genetically modified mouse , cardiology , fibrosis , transgene , chemistry , ejection fraction , biochemistry , blood pressure , gene , atpase , enzyme
Background Heart failure (HF) with preserved ejection fraction (HFpEF) is characterized by a preserved cardiac EF, the presence of HF symptoms and diastolic dysfunction. There is a lack of animal models for exploring the mechanisms and treatments of HFpEF. Cardiomyocytes (CMs) specific, inducible Cavβ2a low expression transgenic (Cavβ2a LE TG) mice have increased cytosolic Ca 2+ . Hypothesis Cavβ2a LE TG mice treated with high‐fat diet (HFD) and L‐Name could be a model for HFpEF. Methods Cavβ2a LE TG mice were studied since transgene expression at the age of 4 months. LE and control mice with chow diet were euthanized for myocyte function and histological analyses, and Western blotting measurements to prove the gene expression. LE and control mice were treated with either chow diet (LC and CC), HFD+L‐Name (LHL, CHL), or HFD+L‐Name+SAHA (LHLS, CHLS) for 6 months. Echocardiography had been done monthly to evaluate the systolic and diastolic function. Results LE TG ventricular myocytes (VMs) had greater Ca 2+ currents at the age of 4m (LE increased by 95.5%; HE increased by 171.9%) and maintained at a similar level at the age of 10m. VM contraction and calcium transients had greater amplitudes in TG than in control VMs while the time from the peak contraction to 90% relaxation and the tau of Ca 2+ transient decay of VMs were not different between groups probably due to enhanced NCX expression and increased SERCA activity because of increased phospholamban phosphorylation at the Thr17 site. More fibrosis of the LV tissue, cardiomyocytes necrosis was observed in LE hearts than control heart. Six months after treatment, LE mice with chow diet had the highest mortality rate than other groups (LC: 37.5%, LHL: 20%, LHLS: 0%, CC:5%; CHL: 25%, CHLS:0%). EF was higher in LE mice before and 1 month after treatment, but decreased to the same (>50%) as in control mice. Left atrial (LA) dilation rate, as an indicator for cardiac diastolic function, was highest in LHL mice (90%), followed by LC mice (24.4%). LHLS mice did not have LA dilation, which indicated SAHA could reverse the LA dilation. The ratio of mitral E wave to mitral annulus e’ velocity (E/e’ ratio) was higher in LHL mice when compared with CHL mice. LHL and LHLS mice had lower left ventricular wall relaxation rates, as indicated by smaller reversed radial and circumferential strain rates. Conclusion When treated with HFD and L‐Name, LE mice, but not control mice, showed preserved systolic function with the progression to diastolic dysfunction, which could be reversed by SAHA to some extent. The lower mortality rate in LE+HFD+L‐Name mice could relate to the obesity paradox, worthy of further study. The Cavβ2a LE TG mouse treated with HFD and L‐Name is a model for HFpEF for exploring HF pathobiology and mechanisms.