Diabetic cardiomyopathy (DCM) is highly prevalent in
type 2 diabetes (T2DM) patients.
Zinc is an important essential trace
metal, whose deficiency is associated with various chronic ailments, including
vascular diseases. We assessed T2DM B6.BKS(D)-Leprdb/J (db/db) mice fed for six months on a normal diet containing three
zinc levels (deficient, adequate, and supplemented), to explore the role of
zinc in DCM development and progression. Cardiac function, reflected by ejection fraction, was significantly decreased, along with increased left ventricle mass and heart weight to tibial length ratio, in db/db mice. As a molecular
cardiac hypertrophy marker,
atrial natriuretic peptide levels were also significantly increased. Cardiac dysfunction and
hypertrophy were accompanied by significantly increased fibrotic (elevated
collagen accumulation as well as
transforming growth factor β and
connective tissue growth factor levels) and inflammatory (enhanced expression of
tumor necrosis factor alpha,
interleukin-1β, caspase recruitment domain family member 9, and
B-cell lymphoma/
leukemia 10, and activated
p38 mitogen-activated protein kinase) responses in the heart. All these diabetic effects were exacerbated by
zinc deficiency, and not affected by
zinc supplementation, respectively. Mechanistically, oxidative stress and damage, mirrored by the accumulation of
3-nitrotyrosine and
4-hydroxy-2-nonenal, was significantly increased along with significantly decreased expression of Nrf2 and its downstream
antioxidants (NQO-1 and
catalase). This was also exacerbated by
zinc deficiency in the db/db mouse heart. These results suggested that
zinc deficiency promotes the development and progression of DCM in T2DM db/db mice. The exacerbated effects by
zinc deficiency on the heart of db/db mice may be related to further suppression of Nrf2 expression and function.