The genetic and metabolic determinants of cardiovascular complications in type 2 diabetes: recent insights from animal models and clinical investigations.

Cardiovascular complications (CVC) are the most common causes of death in patients with type 2 diabetes (T2D). However the pathophysiological determinants and molecular mechanisms involved in the progression of CVC in T2D are poorly understood. We have undertaken the challenging task of identifying some of the genetic and clinical determinants of CVC through a unique multidisciplinary approach involving Canadian and Finnish investigators.

AMPK activation through mitochondrial regulation results in increased substrate oxidation and improved metabolic parameters in models of diabetes.

Modulation of mitochondrial function through inhibiting respiratory complex I activates a key sensor of cellular energy status, the 5'-AMP-activated protein kinase (AMPK). Activation of AMPK results in the mobilization of nutrient uptake and catabolism for mitochondrial ATP generation to restore energy homeostasis. How these nutrient pathways are affected in the presence of a potent modulator of mitochondrial function and the role of AMPK activation in these effects remain unclear.

Distinct metabolic and vascular effects of dietary triglycerides and cholesterol in atherosclerotic and diabetic mouse models.

Cholesterol and triglyceride-rich Western diets are typically associated with an increased occurrence of type 2 diabetes and vascular diseases. This study aimed to assess the relative impact of dietary cholesterol and triglycerides on glucose tolerance, insulin sensitivity, atherosclerotic plaque formation, and endothelial function. C57BL6 wild-type (C57) mice were compared with atherosclerotic LDLr(-/-) ApoB(100/100) (LRKOB100) and atherosclerotic/diabetic IGF-II × LDLr(-/-) ApoB(100/100) (LRKOB100/IGF) mice.

Cyclo-oxygenase-2 knockout genotype in mice is associated with blunted angiotensin II-induced oxidative stress and hypertension.

Background: Inflammation and oxidative stress have been identified as integral parts in the pathogenesis of hypertension. Cyclo-oxygenase-2 which could elicit inflammation and free radicals generation appears to be a key enzyme in hypertension. Cyclo-oxygenase-2 expression and oxidative stress in cardiovascular tissues are increased in the angiotensin II model.

Contribution of gene-modified mice and rats to our understanding of the cardiovascular pharmacology of serotonin.

This review focuses on new insights provided by gene-modified animals into the cardiovascular pharmacology of serotonin. During their development, mice mutant for tryptophan hydroxylase 1 and lacking peripheral serotonin, or mutant for 5-HT(2B) receptors, display cardiac defects and dilated cardiomyopathy. The 5-HT(4) receptor is important for the maturation of cardiac conduction.

The purinergic P2Y1 receptor supports leptin secretion in adipose tissue.

Extracellular nucleotides have been shown to trigger intracellular calcium release and influence leptin secretion in differentiated white and brown adipocytes through activation of various but not clearly identified P2 receptors. In the present study, we wished to assess whether or not the P2Y1 ADP receptor is functional in white adipocytes and whether it could affect the secretion of adipocyte-derived hormones. Stromal cells and mature adipocytes were isolated from epididymal adipose tissue from wild-type and P2Y1 knockout (KO) C57-black/six male mice.

Serotonin 5-HT(2B) receptor blockade prevents reactive oxygen species-induced cardiac hypertrophy in mice.

We established previously that 5-HT(2B) receptors are involved in cardiac hypertrophy through the regulation of hypertrophic cytokines in cardiac fibroblasts. Moreover, the generation of reactive oxygen species and tumor necrosis factor-alpha through the activation of reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase has been implicated in cardiac hypertrophy. In this study, we investigated whether 5-HT(2B) receptors could be involved in the development of cardiac hypertrophy associated with superoxide anion production.

The interrelation of the angiotensin and endothelin systems on the modulation of NAD(P)H oxidase.

The NAD(P)H oxidase is an enzyme assembled at the cellular membrane able to produce superoxide anion from NADH or NAD(P)H (nicotinamide adenine dinucleotide phosphate). It is one of the main sources of superoxide anion in cardiovascular tissues and its role in a variety of cardiovascular disorders such as atherosclerosis, cardiac hypertrophy, and endothelial dysfunction was recently proposed. Although, many factors and receptors were shown to lead to the activation of the enzyme, particulary the type 1 angiotensin receptor, the pathways involved are still widely unknown.

Cyclooxygenase-2 inhibitors attenuate angiotensin II-induced oxidative stress, hypertension, and cardiac hypertrophy in rats.

Angiotensin II is an important oxidative stress mediator. Our previous studies have indicated that the potent antioxidative properties of acetylsalicylic acid play an important role in its cardiovascular protective effects. There are some ongoing controversies concerning the use of selective cyclooxygenase-2 inhibitors in cardiovascular disease.

Oxidative stress in hypertension.

Several experimental and clinical evidences have linked an enhanced production of reactive oxygen species (ROS) to certain diseases of the cardiovascular system including hypertension and diabetes. However, it has never been clearly established whether the enhanced oxidative stress observed in those conditions is primary or secondary to the pathological process. Our experimental studies have permitted to demonstrate that ROS, mainly through the production of superoxide anion, can cause important alterations in the cellular signal transduction systems characterized by an enhanced production of inositol triphosphate and a reduced production of cyclic GMP in cultured vascular smooth muscle cells (SMC), thus favouring the vasoconstriction.

Endothelin mediates superoxide production in angiotensin II-induced hypertension in rats.

Angiotensin II and endothelin-1 (ET) are two hormones involved in cardiovascular diseases and well known for their capacity to induce free radical generation in vascular and cardiac tissues. In addition to its prooxidative effect, angiotensin II can increase the synthesis of ET-1 in vascular smooth muscle cells (VSMC). Our objective was to determine whether the ET-1 synthesis in VSMC is involved in angiotensin II-induced superoxide anion production in rats.

Prevention of angiotensin II-induced hypertension, cardiovascular hypertrophy and oxidative stress by acetylsalicylic acid in rats.

Background: Angiotensin II (Ang II)-induced oxidative stress has been suspected to play an important part in the pathogenesis of many cardiovascular diseases. Our previous study demonstrated that acetylsalicylic acid (ASA) possesses potent antioxidative properties.

Objective: To evaluate the pathogenetic role of oxidative stress in Ang II-induced hypertension and cardiovascular hypertrophy.

NAD(P)H oxidase activation by angiotensin II is dependent on p42/44 ERK-MAPK pathway activation in rat's vascular smooth muscle cells.

Objective: To determine whether the activation of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase and the increase of superoxide anion production by angiotensin II is dependent upon the activation of the ERK-MAPK pathway.

Methods: Hypertension was induced in Sprague-Dawley rats by infusing angiotensin II (200 ng/kg per min) through osmotic pumps for 12 days. The effects of treatments including an angiotensin II type 1 (AT(1)) blocker losartan (20 mg/kg per day), a tyrosine kinase inhibitor genistein (1.

Comparison of the cardiovascular protection by omapatrilat and lisinopril treatments in DOCA-salt hypertension.

Objective: To compare the cardiovascular protection provided by omapatrilat and lisinopril in an experimental model of hypertension.

Methods: Four-week deoxycorticosterone acetate (DOCA)-salt hypertensive (HT) and age-matched normotensive (NT) rats were treated either with omapatrilat (40 mg/kg per day) or lisinopril (20 mg/kg per day) for 2 weeks before sacrifice, and compared with untreated HT and NT rats sacrificed at ages corresponding to either before or after the drug regimens.

Results: Systolic arterial pressure (SAP) of 2 and 4 week HT rats was increased in comparison to age-matched NT rats (P <0.