Insulin-induced generation of reactive oxygen species and uncoupling of nitric oxide synthase underlie the cerebrovascular insulin resistance in obese rats.

Hyperinsulinemia accompanying insulin resistance (IR) is an independent risk factor for stroke. The objective is to examine the cerebrovascular actions of insulin in Zucker obese (ZO) rats with IR and Zucker lean (ZL) control rats. Diameter measurements of cerebral arteries showed diminished insulin-induced vasodilation in ZO compared with ZL.

Mechanisms of cardiovascular remodeling in hyperhomocysteinemia.

In hypertension, an increase in arterial wall thickness and loss of elasticity over time result in an increase in pulse wave velocity, a direct measure of arterial stiffness. This change is reflected in gradual fragmentation and loss of elastin fibers and accumulation of stiffer collagen fibers in the media that occurs independently of atherosclerosis. Similar results are seen with an elevated level of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), which increases vascular thickness, elastin fragmentation, and arterial blood pressure.

Functional consequences of the collagen/elastin switch in vascular remodeling in hyperhomocysteinemic wild-type, eNOS-/-, and iNOS-/- mice.

A decrease in vascular elasticity and an increase in pulse wave velocity in hyperhomocysteinemic (HHcy) cystathionine-beta-synthase heterozygote knockout (CBS(-/+)) mice has been observed. Nitric oxide (NO) is a potential regulator of matrix metalloproteinase (MMP) activity in MMP-NO-tissue inhibitor of metalloproteinase (TIMP) inhibitory tertiary complex. However, the contribution of the nitric oxide synthase (NOS) isoforms eNOS and iNOS in the activation of latent MMP is unclear.

Renal mitochondrial damage and protein modification in type-2 diabetes.

Although mitochondrial reduction-oxidation (redox) stress and increase in membrane permeability play an important role in diabetic-associated renal microvasculopathies, it is unclear whether the intra-renal mitochondrial oxidative stress induces mitochondrial protein modifications, leading to increase mitochondrial membrane permeability. The hypothesis is that mitochondrial oxidative stress induces mitochondrial protein modification and leakage in the mitochondrial membrane in type-2 diabetes. The present study was conducted to determine the involvement of intra-renal mitochondrial oxidative stress in mitochondrial protein modifications and modulation of membrane permeability in the setting of type-2 diabetes.

Cardiac dys-synchronization and arrhythmia in hyperhomocysteinemia.

Although cardiac synchronization is important in maintaining myocardial performance, the mechanism of dys-synchronization in ailing to failing myocardium is unclear. It is known that the cardiac myocyte contracts and relaxes individually; however, it synchronizes only when connected to one another by low resistance communications called gap junction protein (connexins) and extra cellular matrix (ECM). Therefore, the remodeling of connexins and ECM in heart failure plays an important role in cardiac conduction, synchronization and arrhythmias.

3-Deazaadenosine mitigates arterial remodeling and hypertension in hyperhomocysteinemic mice.

Chronic hyperhomocysteinemia (HHcy) is an important factor in development of arterial hypertension. HHcy is associated with activation of matrix metalloproteinases (MMPs); however, it is unclear whether HHcy-dependent extracellular matrix (ECM) accumulation plays a role in arterial hypertrophy and hypertension. We tested the hypothesis that in HHcy the mechanism of arterial hypertension involves arterial dysfunction in response to ECM accumulation between endothelial and arterial smooth muscle cells and subsequent endothelium-myocyte (E-M) uncoupling.