Hsp22 Deficiency Induces Age-Dependent Cardiac Dilation and Dysfunction by Impairing Autophagy, Metabolism, and Oxidative Response

Abstract

Heat shock protein 22 (Hsp22) is a small heat shock protein predominantly expressed in skeletal and cardiac muscle. Previous studies indicate that Hsp22 plays a vital role in protecting the heart against cardiac stress. However, the essential role of Hsp22 in the heart under physiological conditions remains largely unknown. In this study, we used an Hsp22 knockout (KO) mouse model to determine whether loss of Hsp22 impairs cardiac growth and function with increasing age under physiological conditions. Cardiac structural and functional alterations at baseline were measured using echocardiography and invasive catheterization in Hsp22 KO mice during aging transition compared to their age-matched wild-type (WT) littermates. Our results showed that Hsp22 deletion induced progressive cardiac dilation along with declined function during the aging transition. Mechanistically, the loss of Hsp22 impaired BCL-2–associated athanogene 3 (BAG3) expression and its associated cardiac autophagy, undermined cardiac energy metabolism homeostasis and increased oxidative damage. This study showed that Hsp22 played an essential role in the non-stressed heart during the early stage of aging, which may bring new insight into understanding the pathogenesis of age-related dilated cardiomyopathy.

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

“…In addition, HSP22 was also found to be involved in the metabolic switch in the ischemic heart by promoting the activity of 5′ AMP-activated protein kinase (AMPK), which subsequently stimulates glucose uptake and glycolysis to compensate for the lack of aerobic ATP production in the ischemic heart [ 20 , 36 ]. A most recent study showed that loss of HSP22 impaired fatty acid (FA) and glucose metabolism by interfering with the critical regulatory enzymes in FA transport and FA oxidation (FAO) and with glycolysis and gluconeogenesis, respectively, undermining ATP production in physiological aging transition, leading to cardiac dilation and dysfunction [ 26 ].…”

“…BAG3 has been reported to act in concert with HSP22 to induce autophagic degradation, especially in cardiomyocytes [ 20 ]. On the other hand, a study showed that deletion of HSP22 reduced the expression of BAG3 and impaired cardiac autophagy in the aging heart [ 26 ].…”

“…In addition, HSP22 overexpression attenuates ROS production in isolated mitochondria from the cardiomyocytes from HSP22 TG mice. 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. These opposite observations [ 26 , 44 ] may also be due to the difference in the expression level and affected period of HSP22. For example, moderate increase and short-term effect of HSP22 result in a reduction in ROS and attenuation of oxidative stress, such as in isolated culture cells [ 22 ] or young mouse heart [ 26 ], while the extremely high-level expression and long-term chronic effect of HSP22 increases ROS production, as observed in aged TG mice [ 44 ].…”

“…Reciprocally, the knockdown of HSP22 increases stress-induced cardiomyocyte death and accelerates the transition into heart failure [ 25 ]. One more recent study also showed that the loss of HSP22 progressively induced cardiac dilation and dysfunction [ 26 ]. All these studies have highlighted the importance of HSP22 in the heart under both physiological and pathological conditions.…”