Abstract
Diabetes mellitus is a chronic metabolic condition that affects carbohydrate, lipid and protein metabolism and may impair numerous organs and functions of the organism. Cardiac dysfunction afflicts many patients who experience the oxidative stress of the heart. Diabetic cardiomyopathy (DCM) is one of the major complications that accounts for more than half of diabetes-related morbidity and mortality cases. Chronic hyperglycemia and hyperlipidemia from diabetes mellitus cause cardiac oxidative stress, endothelial dysfunction, impaired cellular calcium handling, mitochondrial dysfunction, metabolic disturbances, and remodeling of the extracellular matrix, which ultimately lead to DCM. Although many studies have explored the mechanisms leading to DCM, the pathophysiology of DCM has not yet been fully clarified. In fact, as a potential mechanism, the associations between DCM development and mitogen-activated protein kinase (MAPK) activation have been the subjects of tremendous interest. Nonetheless, much remains to be investigated, such as tissue- and cell-specific processes of selection of MAPK activation between pro-apoptotic vs. pro-survival fate, as well as their relation with the pathogenesis of diabetes and associated complications. In general, it turns out that MAPK signaling pathways, such as extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK) and p38 MAP kinase, are demonstrated to be actively involved in myocardial dysfunction, hypertrophy, fibrosis and heart failure. As one of MAPK family members, the activation of ERK1/2 has also been known to be involved in cardiac hypertrophy and dysfunction. However, many recent studies have demonstrated that ERK1/2 signaling activation also plays a crucial role in FGF21 signaling and exerts a protective environment of glucose and lipid metabolism, therefore preventing abnormal healing and cardiac dysfunction. The duration, extent, and subcellular compartment of ERK1/2 activation are vital to differential biological effects of ERK1/2. Moreover, many intracellular events, including mitochondrial signaling and protein kinases, manipulate signaling upstream and downstream of MAPK, to influence myocardial survival or death. In this review, we will summarize the roles of ERK1/2 pathways in DCM development by the evidence from current studies and will present novel opinions on “differential influence of ERK1/2 action in cardiac dysfunction, and protection against myocardial ischemia-reperfusion injury”.
Highlights
Diabetes mellitus (DM) is one of the world’s most common metabolic disorders
The results showed that High glucose (HG) increased cell size and hypertrophy gene expressions, and was accompanied by elevating the expression of extracellular signal-regulated kinase 1/2 (ERK1/2) but not of p38 mitogen-activated protein kinase (MAPK) or Jun N-terminal protein kinase (JNK) activity
Authors checked the anti-fibrosis effect of resveratrol, an antioxidant. They observed that transforming growth factor beta (TGF-β) and p-ERK1/2 were elevated in the condition of HG, while the HG-induced up-regulation of TGF-β was suppressed by U0126, suggesting the involvement of ERK1/2 in HG-induced TGF-β expression [65,66]
Summary
Diabetes mellitus (DM) is one of the world’s most common metabolic disorders. The number of global diabetic patients rose to 415 million in 2015 [1], about 8.3% of the adult population [2]. EERRKK11//22 ssiiggnnaalliningg iiss ccllaassssiiccaallllyy ttrriiggggeerreedd bbyy aaccttiivvaattiioonn ooff tthhee ssmmaallll GG--pprrootteeiinn RRaass aatt tthhee mmyyooccyyttee mmeennbbrraannee,, wwhhiicchh tthheenn rreeccrruuiittss aanndd aaccttiivvaatteess cc--RRaaff,, aa MMAAPP33KK A large amount of evidence reveals the role of the ERK1/2 signaling cascade in the development of DCM, most of which suggests that ERK1/2 activation plays a detrimental role in the process of oxidative stress, inflammation, remodeling and apoptosis in the diabetic heart. Of evidence reveals the role of the ERK1/2 signaling cascade in the development of DCM, most of which suggests that ERK1/2 activation plays a detrimental role in the process of oxidative stress, inflammation, remodeling and apoptosis in the diabetic heart. Despite the pro-apoptotic role of ERK1/2 in diabetes settings, the pro-survival effect of ERK1/2, which protects from cardiac injury induced by I/R and MI on the diabetic heart, has been noted
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