Metformin ameliorates gender-and age-dependent hemodynamic instability and myocardial injury in murine hemorrhagic shock

Abstract

Severity of multiple organ failure is significantly impacted by age and gender in patients with hemorrhagic shock. However, the molecular mechanisms underlying the enhanced organ injury are not fully understood. AMP-activated protein kinase (AMPK) is a pivotal orchestrator of metabolic responses during stress. We investigated whether hemorrhage-induced myocardial injury is age and gender dependent and whether treatment with metformin, an AMPK activator, affords cardioprotective effects. C57/BL6 young (3–5 months) and mature (9–12 months) male and female mice were subjected to hemorrhagic shock by blood withdrawing followed by resuscitation with blood and Lactated Ringer’s solution. Vehicle-treated young and mature mice of both genders had a similar elevation of plasma inflammatory cytokines at 3 hours after resuscitation. However, vehicle-treated male mature mice experienced hemodynamic instability and higher myocardial damage than young male mice, as evaluated by echocardiography, histology and cardiovascular injury biomarkers. There was also a gender-dependent difference in cardiovascular injury in the mature group as vehicle-treated male mice exhibited more severe organ injury than female mice. At molecular analysis, vehicle-treated mature mice of both genders exhibited a marked downregulation of AMPKα activation and nuclear translocation of peroxisome proliferator-activated receptor γ co-activator α when compared with young mice. Treatment with metformin improved cardiovascular function and survival in mature animals of both genders. However, specific cardioprotective effects of metformin were gender-dependent. Metformin did not affect hemodynamic or inflammatory responses in young animals. Thus, our data suggest that targeting metabolic recovery with metformin may be a potential treatment approach in severe hemorrhage in adult population.

Metformin Exerts Beneficial Effects in Hemorrhagic Shock in An AMPKα1-Independent Manner

“…We have previously shown that pharmacological activation of AMPK with a synthetic AMP monolog AICAR can exert lung and cardiac protective effects and improve the hemodynamic compensatory mechanisms in a murine hemorrhagic shock model (8, 9). Similarly, we have previously described that treatment with metformin ameliorates myocardial damage in middle-aged (9–12 months old) mice subjected to severe hemorrhage (23). Conversely, in this study, we demonstrated that absence of AMPKα1 in genetically deficient mice worsened the hemodynamic instability, the systemic inflammatory response, and the liver and lung injury after hemorrhagic shock when compared to mice with a functional AMPKα1, thus suggesting that AMPKα1 is an important requisite for regulating the metabolic response as well as the hemodynamic performance during hemorrhagic shock.…”

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