Heat Shock Protein 27 Modification is Increased in the Human Diabetic Failing Heart

Abstract

Chronic conditions like diabetes mellitus (DM) leading to altered metabolism might cause cardiac dysfunction. Hyperglycemia plays an important role in the pathogenesis of diabetic complications including accumulation of methylglyoxal (MG), a highly reactive alpha-dicarbonyl metabolite of glucose degradation pathways and increased generation of advanced glycation endproducts (AGEs). The aim of this investigation was to study the extent of the MG-modification argpyrimidine in human diabetic heart and in rat cardiomyoblasts grown under hyperglycemic conditions. Left ventricular myocardial samples from explanted hearts of patients with cardiomyopathy with (n=8) or without DM (n=8) as well as nonfailing donor organs (n=6), and rat cardiac myoblasts H9c2 treated with glucose were screened for the MG-modification argpyrimidine. The small heat shock protein 27 (Hsp27) revealed to be the major argpyrimidine containing protein in cardiac tissue. Additionally, the modification of arginine leading to argpyrimidine and the phosphorylation of Hsp27 are increased in the myocardium of patients with DM. In H9c2 cells hyperglycemia leads to a decrease of the Hsp27-expression and an increase in argpyrimidine content and phosphorylation of Hsp27, which was accompanied by the induction of oxidative stress and apoptosis. This study shows an association between diabetes and increased argpyrimidine-modification of myocardial Hsp27, a protein which is involved in apoptosis, oxidative stress, and cytoskeleton stabilization.

Atorvastatin alleviates experimental diabetic cardiomyopathy by suppressing apoptosis and oxidative stress

“…The crosslink in collagen and elastin increases myocardial stiffness, and impairs its relaxation (Petrova et al 2002;Gawlowski et al 2009). This results in activation of transcription factors, such as nuclear factor-kB (NF-kB) which up-regulates genes that increase the local inflammatory cytokines causing myocardial damage (Burgess et al 2001;Chen et al 2008;Guleria et al 2013;Palomer et al 2013).…”

Diabetic cardiomyopathy: where we are and where we are going

“…The crosslinking involving elastin and collagen results in impaired cardiac relaxation and increased myocardial stiffness. AGEs cause myocardial damage in both humans [22] and animals [23]. …”

Hyperglycemia-mediated activation of the hexosamine biosynthetic pathway results in myocardial apoptosis

“…In support, others (24) found that hyperglycemia-induced ROS production in renal cells mediates apoptosis and contributes to diabetic nephropathy. Moreover, diabetic rats display increased expression of genes involved in oxidative stress and apoptosis, e.g., upregulation of Txnip, a negative regulator of the antioxidant thioredoxin and p53 pathway members (15), while H9c2 myoblasts exposed to high glucose levels exhibit decreased expression of heat shock protein 27, resulting in oxidative stress and apoptosis (14). We strengthened our data by including an antioxidant, i.e., 4-OHCA treatment attenuated ROS levels observed under both hyper- C145 glycemic conditions and with PUGNAc treatment (note: 4-OHCA decreases mitochondrial pyruvate uptake and hence attenuates oxidative stress).…”