Abstract
Cardiovascular complications are the most prevalent cause of morbidity and mortality in diabetic patients. Metformin is currently the first-line blood glucose-lowering agent with potential relevance to cardiovascular diseases. However, the underpinning mechanisms of action remain elusive. Here, we report that metformin represses cardiac apoptosis at least in part through inhibition of Forkhead box O1 (FoxO1) pathway. In a mouse model of ischemia-reperfusion (I/R), treatment with metformin attenuated cardiac and hypertrophic remodeling after 14 days of post-reperfusion. Additionally, cardiac expression of brain-like natriuretic peptide (BNP) was significantly reduced in metformin-treated mice after 14 days of cardiac I/R. In cultured H9C2 cells, metformin counteracted hypertrophic and apoptotic responses to metabolic or hypoxic stress. FoxO1 silencing by siRNA abolished anti-apoptotic effect of metformin under hypoxic stress in H9C2 cells. Taken together, these results suggest that metformin protects the heart against hypertrophic and apoptotic remodeling after myocardial infarction.
Highlights
The most prevalent form of diabetes mellitus in patients is type 2 diabetes (T2D) (Kannel and McGee, 1979)
We show that metformin counteracts myocardial hypertrophy and apoptosis in a mouse model of cardiac I/R
We show that metformin could protect against stress-induced cardiac apoptosis through Forkhead box O1 (FoxO1) pathway
Summary
The most prevalent form of diabetes mellitus in patients is type 2 diabetes (T2D) (Kannel and McGee, 1979). Extended cardiac hypertrophy as a consequence of pathological stress leads to excessive production of reactive oxygen species, activation of apoptotic and inflammatory cascades which play a key role in DCM (Borner and Monney, 1999; Hunter and Chien, 1999; Clerk et al, 2003). These processes results in initiation of pro-fibrotic reprogramming and impaired cardiac function (Wynn and Ramalingam, 2012). We show that metformin could protect against stress-induced cardiac apoptosis through FoxO1 pathway
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