Hsp22 overexpression induces myocardial hypertrophy, senescence and reduced life span through enhanced oxidative stress

Abstract

H11 kinase/Hsp22 (Hsp22) is a small heat shock protein, which, when overexpressed cardiac specifically in transgenic (TG) mice, induces stable left ventricular (LV) hypertrophy. Hsp22 also increases oxidative phosphorylation and mitochondrial reactive oxygen species (ROS) production, mechanisms mediating LV hypertrophy, senescence and reduced lifespan. Therefore, we investigated whether ROS production mediates LV hypertrophy, senescence and reduced life span in Hsp22 TG mice. Survival curves revealed that TG mice had a 48% reduction in their mean life span compared to wild type (WT) mice. This was associated with a significant increase in senescence markers, such as p16, p19 mRNA levels as well as the percentage of β-galactosidase positive cells and telomerase activity. Oxidized (GSSG)/reduced (GSH) glutathione ratio, an indicator of oxidative stress, and ROS production from 3 major cellular sources was measured in cardiac tissue. Hearts from TG mice exhibited a decrease in GSH/GSSG ratio together with increased ROS production from all sources. To study the role of ROS, mice were treated with the antioxidant Tempol from weaning to their sacrifice. Chronic Tempol treatment abolished oxidative stress and overproduction of ROS, and reduced myocardial hypertrophy and Akt phosphorylation in TG mice. Tempol also significantly extended life span and prevented aging markers in TG mice. Taken together these results show that overexpression of Hsp22 increases oxidative stress responsible for the induction of hypertrophy and senescence and ultimately reduction in life span.

Delphinidin attenuates pathological cardiac hypertrophy via the AMPK/NOX/MAPK signaling pathway

“…The hallmarks of cardiac aging include cardiomyocyte senescence, fibroblast proliferation, inflammation, and hypertrophy. Imbalance between the levels of ROS and antioxidant enzymes is greatly enhanced in aging cells, promoting cardiac remodeling [47]. According to our findings, elevated AMPK activity and downregulated NOX expression were observed in the hearts of aging mice compared with young littermates, and delphinidin reversed these phenotypes and improved cardiac function in aging mice.…”

LOX-1 Deletion Attenuates Myocardial Fibrosis in the Aged Mice, Particularly Those With Hypertension

“…ROS are potent stimulators for collagen synthesis and secretion from cardiac fibroblasts and inducers for myocardial fibrosis ( 26 ). Aging and LOX-1 expression both cause ROS production in the hearts ( 18 , 27 ). Our data showed that LOX-1 deletion inhibited ROS production in the hearts of both the aged mice and the aged mice concurrently with hypertension.…”

Heat Shock Protein 22 in Physiological and Pathological Hearts: Small Molecule, Large Potentials

“…Loss of HSP22 results in age-dependent accumulation of oxidative cytotoxic products in the heart, leading to cardiac oxidative damage in older HSP22 KO mice [ 26 ]. Paradoxically, studies also showed that, under the normoxia condition, overexpression of HSP22 increases ROS production, which may be associated with the increased activity and expression of NADPH oxidase 2 (Nox2) and the enhanced activity of xanthine oxidase in the myocardium [ 44 ]. These data indicate that the role of Hsp22 under the physiological condition differs from that under the oxidative stress in the heart and further supports the concept that Hsp22 is a stress-associated protein in the heart that has a distinct protective effect under oxidative stress.…”