Hind Limb Ischemia-Reperfusion in the Leptin Receptor Deficient (db/db) Mouse

Entabi, Fateh; Albadawi, Hassan; Stone, David H.; Sroufe, R.; Conrad, Mark F.; Watkins, Michael T.

doi:10.1016/j.jss.2006.08.008

Cited by 9 publications

(9 citation statements)

References 42 publications

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“…However, compromised muscle regeneration in the context of diseased condition such as aging or diabetes may lead to impaired healing, permanent loss of muscle mass, and functional deficiency. Pathologically, normal muscle regeneration can be hampered by persistent and robust inflammation followed by fibrosis and significant lipid accumulation (6–8). Obesity or metabolic syndrome plays a significant in the development of type II diabetes and cardiovascular disease and the associated comorbidity (9–13).…”

Section: Introductionmentioning

confidence: 99%

Hind limb ischemia–reperfusion injury in diet-induced obese mice

Albadawi

Öklü

Cormier

et al. 2014

Journal of Surgical Research

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Background Obesity is a major risk factor for the development of diabetes. Limb ischemia reperfusion injury (IR) is a common clinical problem in diabetics who have compromised lower extremity perfusion. This study compared the histologic, metabolic and functional outcomes following hindlimb IR in diet-induced obese(DIO) and non-diabetic (ND) mice during the acute and the regenerative phases of IR. Methods DIO and ND mice were subjected to 1.5hrs unilateral hindlimb ischemia followed by 1 or 28 days IR. Muscle morphology, metabolic and genomic stress was evaluated at day 1 and 28 IR; Acute inflammation and thrombosis were only measured at day 1 IR. At day 28 IR, skeletal muscle contractility and maturation was also assessed. Results At day 1 IR, similar levels of acute muscle fiber necrosis were seen in both groups. DIO mice demonstrated substantially greater inflammatory, pro-thrombotic, and genomic stress responses which were also associated with a greater reduction in energy substrates and Akt phosphorylation. At 28 days, there was no difference in the peak forces generated in the hindlimbs for the two groups. DIO mice had reduced fatigue resistance compared to ND and larger areas of fat accumulation even though there was no significant difference in muscle fiber maturation. Conclusion DIO mice had an exacerbated acute response to IR with enhanced metabolic deficit, fat accumulation and defective functional recovery during the regenerative phase of IR. These changes in fatigue resistance reflect compromised functional recovery following IR injury and have relevance for the functional recovery of patients with metabolic syndrome and insulin resistance.

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Section: Introductionmentioning

confidence: 99%

Hind limb ischemia–reperfusion injury in diet-induced obese mice

Albadawi

Öklü

Cormier

et al. 2014

Journal of Surgical Research

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“…1, 2 Diabetes is a powerful risk factor for coronary artery disease, stroke and peripheral arterial disease. 3 It has been reported that endothelial function and myogenic tone are impaired in type 2 diabetes. 2, 4 Limited studies to reveal the mechanisms underlying vascular dysfunction in diabetes have been conducted.…”

Section: Introductionmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase 1 Inhibition Improves Coronary Arteriole Function in Type 2 Diabetes Mellitus

et al. 2012

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Type 2 diabetes (T2D) is associated with microvascular dysfunction. We hypothesized that increased Poly - (ADP-ribose) polymerase-1 (PARP-1) activity contributes to microvascular dysfunction in T2D. T2D (db-/db-) and non-diabetic control (db-/db+) mice were treated with two different PARP-1 inhibitors (INO-1001, 5 mg/Kg/day and ABT-888, 15 mg/Kg/day) for two weeks. Isolated coronary arterioles (CA) were mounted in an arteriograph. Pressure-induced myogenic tone (MT) was significantly potentiated, while endothelium-dependent relaxation (EDR) was significantly attenuated in diabetic mice compared to control. These results were associated with decreased endothelial nitric oxide synthase (eNOS) phosphorylation, cyclic guanosine 3’ 5’-monophosphate (cGMP) level and increased PARP-1 activity in CA from diabetic mice compared to control. Interestingly, PARP-1 inhibitors significantly reduced the potentiation of MT, improved EDR, restored eNOS phosphorylation, cGMP and attenuated cleaved PARP-1. These results were supported by in vitro studies indicating that down-regulation of PARP-1 in mesenteric resistance arteries (MRA) using PARP-1 shRNA lenti-viral particles significantly improved EDR in MRA from diabetic mice compared to control. The inhibition of nitric oxide synthesis by N G-nitro-L-arginine methyl ester (L-NAME) significantly reduced the EDR in CA and MRA from control and diabetic mice treated with PARP-1 inhibitors and PARP-1 shRNA lenti-viral particles. In addition, we demonstrated that enhanced cleaved PARP-1, its binding to DNA and DNA damage were reduced after PARP-1 inhibition in cultured endothelial cells stimulated with high glucose. We provide evidence that T2D impairs microvascular function by an enhanced PARP-1 activity-dependent mechanism. Therefore, PARP-1 could be a potential target for overcoming diabetic microvascular complications.

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“…Macrophages isolated from db/db mice exhibit enhanced inflammatory response and promotion of smooth muscle proliferation, 2 activities acutely ascribed to atherosclerosis [31]. Following an acute occlusion of a vessel, both diabetic patients and db/db mice exhibit limited collateral blood vessel formation as well as reduced secretion of vascular endothelial growth factor [32][33][34].…”

Section: Figmentioning

confidence: 99%