Luteolin Attenuates Diabetic Myocardial Hypertrophy by Inhibiting Proteasome Activity

Abstract

<b><i>Introduction:</i></b> Luteolin is a flavonoid polyphenolic compound exerting broad pharmacological and medicinal properties. Diabetes-related obesity increases the total blood volume and cardiac output and may increase the myocardial hypertrophy progression. However, the mechanism of luteolin in diabetic myocardial hypertrophy remains uncertain. Therefore, this study aimed to evaluate whether luteolin improved diabetic cardiomyopathy (DCM) by inhibiting the proteasome activity. <b><i>Methods:</i></b> Cardiomyopathy was induced in streptozotocin-treated diabetes mellitus (DM) and <i>db/db</i> mice. Luteolin (20 mg kg<sup>−1</sup>·day<sup>−1</sup>) was administrated via gavage for 12 weeks. In vitro<i>,</i> high glucose and high insulin (HGI, glucose at 25.5 mM and insulin at 0.1 µM) inducing primary neonatal rat cardiomyocytes (NRCMs) were treated with or without luteolin for 48 h. Echocardiography, reverse transcription quantitative polymerase chain reaction, histology, immunofluorescence, and Western blotting were conducted. Proteasome activities were also detected using a fluorescent peptide substrate. <b><i>Results:</i></b> Luteolin administration significantly prevented the onset of cardiac hypertrophy, fibrosis, and dysfunction in type 1 DM (T1DM) and type 2 DM (T2DM). Compared with DCM mice, luteolin groups showed lower serum triglyceride and total cholesterol levels. Furthermore, luteolin attenuated HGI-induced myocardial hypertrophy and reduced atrial natriuretic factor mRNA level in NRCMs. Proteasome activities were inhibited by luteolin in vitro. Luteolin also reduces the proteasome subunit levels (PSMB) 1, PSMB2, and PSMB5 of the 20S proteasome, as well as proteasome-regulated particles (Rpt) 1 and Rpt4 levels of 19S proteasome. Furthermore, luteolin treatment increased protein kinase B (AKT) and GSK-3α/β (inactivation of GSK-3) phosphorylation. The phosphorylation level of AMPK activity was also reversed after the treatment with luteolin in comparison with the HGI-treated group. <b><i>Conclusion:</i></b> This study indicates that luteolin protected against DCM in mice, including T1DM and T2DM, by upregulating phosphorylated protein AMPK and AKT/GSK-3 pathways while decreasing the proteasome activity. These findings suggest that luteolin may be a potential therapeutic agent for DCM.

PSMB2 plays an oncogenic role in glioma and correlates to the immune microenvironment

“…PSMB2 is a member of the beta subunit of the proteasome 20S core structure 23 . The 20S proteasome is the catalytic core of the 26S proteasome and the essential enzyme that can degrade ubiquitin-binding proteins 4 .…”

Relationship between the expression of PSMB2 and proliferation and invasion in glioma

“…PSMB2 is a member of the beta subunit of the proteasome 20S core structure [24] . The 20S proteasome is the catalytic core of the 26S proteasome and the essential enzyme that can degrade ubiquitin-binding proteins [4] .…”

A Review on the Natural Products in Treatment of Diabetic Cardiomyopathy (DCM)

“…Table 1 (Ref. [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 ]) provides the basic information and mechanisms of 36 flavonoids from recent studies on DCM, while Fig. 2 shows the chemical structures of the 36 flavonoids.…”

“…The process of cardiac remodeling is influenced by the increase in the activities of proteolytic enzymes [ 111 ]. Luteolin regulates AMPK and AKT/glycogen synthase kinase 3 (GSK-3) signaling pathways and reduces proteasome activity to alleviate cardiac hypertrophy [ 57 ].…”