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2014 ; 192
(1
): 50-8
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Metformin mitigates apoptosis in ischemic myocardium
#MMPMID24969550
Elmadhun NY
; Sabe AA
; Lassaletta AD
; Chu LM
; Sellke FW
J Surg Res
2014[Nov]; 192
(1
): 50-8
PMID24969550
show ga
BACKGROUND: Epidemiologic data has shown that metformin confers a survival
advantage in patients with cardiovascular disease. Although the underlying
cardioprotective mechanism is unclear, it appears to be independent of
metformin's insulin-sensitizing effect. The purpose of this study was to evaluate
the effect of metformin on the apoptosis pathway in the ischemic and nonischemic
cardiac tissue in a swine model of metabolic syndrome. MATERIALS AND METHODS:
Ossabaw miniswine were fed either a regular diet (Ossabaw control, n = 8), a
high-cholesterol diet (Ossabaw high cholesterol, n = 8), or a high-cholesterol
diet supplemented with metformin (Ossabaw high-cholesterol metformin, n = 8).
After 9 wk, all animals underwent placement of an ameroid constrictor to the left
circumflex coronary artery to induce chronic ischemia. Seven weeks after ameroid
placement, animals underwent cardiac harvest. RESULTS: In the chronically
ischemic myocardium, metformin significantly upregulates prosurvival proteins:
extracellular signal-regulated kinases, nuclear factor ?B, phosphorylated
endothelial nitric oxide synthase, and P38. Metformin also significantly inhibits
or downregulates proapoptosis proteins: FOXO3 and caspase 3. Metformin decreased
the percent apoptotic cells in the ischemic and nonischemic myocardium. There was
no difference in arteriolar density, capillary density, intramyocardial fibrosis,
or collagen deposition in the ischemic or nonischemic myocardium. CONCLUSIONS:
Metformin selectively alters the apoptosis pathway by inhibiting FOXO3 and
decreasing the active form of caspase 3, cleaved caspase 3. Metformin also
upregulates mitogen-activated kinase proteins p38 and extracellular
signal-regulated protein kinases 1 and 2, which are considered cardioprotective
during ischemic preconditioning. Perhaps, the altered activation of the apoptosis
pathway in ischemic myocardium is one mechanism by which metformin is
cardioprotective.
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