Abstract Body: Background: Chronic reductive stress (cRS) contributes to adverse cardiac remodeling and diastolic dysfunction; however, the mechanisms remain unclear. Here, we examined how cRS progressively disrupts proteostasis, causing proteotoxicity overtime leading to cardiac remodeling and dyskinesia.
Methods: Cardiac-specific constitutively active Nrf2 transgenic (CaNrf2-TGL/TGH) and NTG mice (n=4–6/group) at ~3 and 6 months of age were studied. NGS-RNA sequencing, speckle tracking strain echocardiography, Proteostat^® histochemistry, and TEM assessed cRS effects on the cardiac transcriptome, endoplasmic reticulum (ER) disintegration, myocardial mechanics, and proteotoxicity. Statistical analyses were performed using Student's t-test.
Results: Protein aggregation in TGH/TGL hearts (≥6 months) indicates cRS-induced misfolding. Altered ER transcriptome and subsarcolemmal ER dilation (TEM analysis) suggest ER stress, leading to myocardial structural and functional disintegration. Longitudinal strain showed moderate to severe endocardial deformation in TGL (p>0.01) and TGH (p>0.0001) vs. NTG at 3 months, while severe segmental dyssynchrony was evident in both TGL and TGH at 6 months. Increased global radial strain and decreased global longitudinal strain in TGH at 3 months (p>0.01) suggest the onset of early dyssynchrony. While TGL at 3 months revealed a moderate myocardial segmental deformation. By 6 months, strain differences emerged in TGL vs. NTG (p>0.001) and worsened in TGH (p>0.0001). TEI index, a measure of global cardiac function, was significantly elevated in both caNrf2-TGL and caNrf2-TGH (2 and 4-fold; P>0.0001) compared to NTG mice (normal index: 0.3-0.6) at 6 months, suggesting impaired systolic and diastolic functions in the RS hearts.
Conclusion: We established a strong correlation between non-amyloid proteotoxicity and cardiac dysfunction under chronic reductive stress, challenging the previous belief that antioxidants are always beneficial.