Increased Antiangiogenic Protein Expression in the Skeletal Muscle of Diabetic Swine and Patients

Abstract

Hypothesis: Antiangiogenic protein expression is increased in skeletal muscle in the setting of diabetes. Design, Setting, and Participants: In animal studies, diabetes was induced in 8 Yucatan miniswine via single alloxan injection at age 8 months, followed by skeletal muscle harvest 15 weeks later. Eight nondiabetic Yucatan miniswine served as controls. In patient studies, skeletal muscle was harvested from 11 nondiabetic patients and 10 patients with type 2 diabetes mellitus undergoing initial elective coronary artery bypass graft surgery. Skeletal muscle samples were analyzed via Western blotting and zymography for protein expression and enzyme activity. The study was performed in an academic medical center. Main Outcome Measures: Skeletal muscle expression of plasminogen, collagen XVIII, angiostatin, endostatin, matrix metalloproteinases 2 and 9, and tissue inhibitor of metalloproteinase 2. Results: Skeletal muscle expression of plasminogen and collagen XVIII (precursors of angiostatin and endostatin, respectively) remained similar between nondiabetic and diabetic swine and patients. Expression of angiostatin and endostatin was increased 1.70-fold and 1.84-fold, respectively, in diabetic swine relative to control swine. Endostatin expression was increased 1.69fold in diabetic patients relative to nondiabetic patients. Matrix metalloproteinase 2 expression and activity were significantly increased in the skeletal muscle of diabetic swine and patients. Conclusions: Antiangiogenic protein levels are increased in the skeletal muscle in the setting of diabetes. Angiostatin, endostatin, and matrix metalloproteinases may offer novel therapeutic targets to improve collateral formation in patients with diabetes.

Anti-angiogenic effect of high-dose resveratrol in a swine model of metabolic syndrome

“…In previous animal and human studies we and others have demonstrated that hypercholesterolemia and diabetes mellitus are detrimental to the native angiogenic process 23. In these studies, like the current work, common comorbid diseases lead to decreased collateral formation in ischemic myocardium and increased anti-angiogenic factor expression.…”

Neuropeptide Y improves myocardial perfusion and function in a swine model of hypercholesterolemia and chronic myocardial ischemia

“…Capillaries (CD31, green), nuclei (DAPI, blue) and arterioles with smooth muscle (actin, red) are stained. *p b 0.05. in the right atrium of patients with type II diabetes mellitus [13,14,33,34]. Interestingly, in a normal-diet swine model of chronic myocardial ischemia, local infiltration of NPY 3-36 significantly decreased the levels of these anti-angiogenic factors [23].…”

“…The associated diffuse coronary artery disease pattern has led to limited success after both percutaneous and surgical treatments [12]. Importantly, apart from the altered angiogenic signaling there is increased anti-angiogenic signaling in this patient population [13,14]. Thus, overcoming the local antiangiogenic milieu in this patient population with inoperable diffuse disease associated with diabetes and metabolic syndrome would be a highly desirable option.…”

Overfed Ossabaw swine with early stage metabolic syndrome have normal coronary collateral development in response to chronic ischemia

“…Thus, it is not surprising that despite successful animal studies in myopreservation, myocardial regeneration, and therapeutic neovascularization in otherwise healthy animals, the transition to successful clinical trials has been met with only modest gains, and little if any clinical impact. Indeed, type 1 diabetes [6], metabolic syndrome (MetS) [12], and hypercholesterolemia [4] are associated with diminished collateral formation and endothelial function in both animals and patients [30, 31, 36]. …”