Cuihua Zhang

Type 2 diabetes (T2D) is a leading risk factor for cardiovascular diseases including atherosclerosis and coronary heart disease. Exercise training (ET) is thought to have a beneficial effect on these disorders, but the basis for this effect is not fully understood. Because endothelial dysfunction plays a key role in the pathological events leading to cardiovascular complications in T2D, we hypothesized that the effects of ET will be evidenced by improvements in coronary endothelial function. To test this hypothesis, we assessed the effects of ET on vascular function of diabetic (db/db, Leprdb) mice by evaluating endothelial function of isolated coronary arterioles of wild-type (WT) and db/db mice with/without ET. Although dilation of vessels to the endothelial-independent vasodilator, sodium nitroprusside was not different between db/db and WT, dilation to the endothelial-dependent agonist, acetylcholine (ACh), was impaired in db/db compared to WT mice. Vasodilation to ACh was restored in db/db with ET and insulin sensitivity was improved in the db/db after ET. Exercise did not change body weight of db/db, but superoxide dismutase (SOD1 and SOD2) and phosphorylated- eNOS protein (Ser1177) expression in heart tissue was up-regulated whereas tumor necrosis factor-alpha (TNF-α) protein level was decreased by ET. Serum level of interleukin-6 (IL-6) was higher in db/db mice but ET decreased IL-6. This suggests that ET may improve endothelial function by increasing nitric oxide bioavailability as well as decreasing chronic inflammation. We suggest this connection may be the basis for the benefit of ET in T2D.

Objective—: Bariatric surgery is emerging as an effective method to alleviate a multitude of medical conditions associated with morbid obesity and type 2 diabetes. However, little is known about the effects and mechanisms of bariatric surgery on visceral fat inflammation and endothelial dysfunction in type 2 diabetes. We hypothesize that bariatric surgery ameliorates interferon-γ–mediated adipose tissue inflammation/oxidative stress and improves endothelial function in type 2 diabetic mice. Methods and Results—: Control mice (m Lepr ^db ) and diabetic mice (Lepr ^db ) were treated with either sham surgery or improved gastric bypass surgery and then were evaluated at 5, 10, 20, and 30 days to assess postsurgical effects. Surgery reduced body weight, abdominal adiposity, blood glucose level, and food intake in Lepr ^db . The surgery-induced decrease in visceral adiposity was accompanied by amelioration of T-lymphocytes and macrophage infiltration, as well as reduction in the expression of interferon-γ and other inflammatory cytokines in the mesenteric adipose tissue (MAT) of Lepr ^db mice. Furthermore, surgery improved endothelium-dependent, but not endothelium-independent, vasorelaxation in small mesenteric arteries (SMA) of Lepr ^db mice. The improvement in endothelial function was largely attenuated by nitric oxide synthase inhibitor (L-NAME) incubation. Interferon-γ treatment increased the mRNA expression of tumor necrosis factor-α in the MAT of control mice and incubation of SMA of control mice with tumor necrosis factor-α caused impairment of endothelial function. Superoxide production in MAT/SMA and nitrotyrosine protein level in SMA were elevated in diabetic mice. Surgery reduced MAT/SMA oxidative stress in Lepr ^db mice. Conclusion—: The amelioration of adipose tissue inflammation and the improvement of endothelial function may represent important mechanisms that result in cardiovascular benefits after bariatric surgery.

Interferon-gamma (IFNγ) has previously been associated with immuno-mediated inflammation in diet-induced obesity and type 1 diabetes. This study sought to define the role of IFNγ-induced adipose tissue inflammation in endothelial dysfunction in type 2 diabetes. We examined mesenteric adipose tissue (MAT) inflammation, and endothelial function of small mesenteric artery (SMA) in control mice (m Lepr^db), diabetic mice (Lepr^db), m Lepr^db treated with IFNγ, and Lepr^db treated with anti-IFNγ or anti-monocyte chemoattractant protein-1 (anti-MCP-1). mRNA and protein expression of IFNγ and MCP-1 were increased in MAT of Lepr^db, accompanied by increased T-lymphocyte and macrophage infiltration. Anti-IFNγ reduced MAT inflammatory cell infiltration and inflammatory cytokine expression in Lepr^db, while IFNγ treatment showed the opposite effects in m Lepr^db. Acetylcholine (ACh)-induced vasorelaxation of SMA was impaired in Lepr^db versus m Lepr^db, but sodium nitroprusside (SNP)-induced vasorelaxation was comparable. Both anti-IFNγ and anti-MCP-1 improved endothelial function of Lepr^db, while IFNγ treatment impaired endothelial function of m Lepr^db. Superoxide production was higher in both MAT and SMA of Lepr^db mice, and anti-IFNγ reduced MAT and SMA superoxide production. Macrophage accumulation in the adventitia of SMA, and mRNA expression of MCP-1 in SMA were increased in Lepr^db and IFNγ-treated m Lepr^db, but reduced in anti-IFNγ treated Lepr^db. These findings suggest IFNγ has a key role in the regulation of visceral adipose tissue inflammatory response and endothelial dysfunction in type 2 diabetes.

Type 2 diabetes (T2D) is a leading risk factor for a variety of cardiovascular diseases including coronary heart disease and atherosclerosis. Exercise training (ET) has a beneficial effect on these disorders, but the basis for this effect is not fully understood. This study was designed to investigate whether the ET abates endothelial dysfunction in the aorta in T2D. Heterozygous controls (m Lepr ^db) and type 2 diabetic mice ( db/db; Lepr ^db) were either exercise entrained by forced treadmill exercise or remained sedentary for 10 wk. Ex vivo functional assessment of aortic rings showed that ET restored acetylcholine-induced endothelial-dependent vasodilation of diabetic mice. Although the protein expression of endothelial nitric oxide synthase did not increase, ET reduced both IFN-γ and superoxide production by inhibiting gp91^phox protein levels. In addition, ET increased the expression of adiponectin (APN) and the antioxidant enzyme, SOD-1. To investigate whether these beneficial effects of ET are APN dependent, we used adiponectin knockout (APNKO) mice. Indeed, impaired endothelial-dependent vasodilation occurred in APNKO mice, suggesting that APN plays a central role in prevention of endothelial dysfunction. APNKO mice also showed increased protein expression of IFN-γ, gp91^phox, and nitrotyrosine but protein expression of SOD-1 and -3 were comparable between wild-type and APNKO. These findings in the aorta imply that APN suppresses inflammation and oxidative stress in the aorta, but not SOD-1 and -3. Thus ET improves endothelial function in the aorta in T2D via both APN-dependent and independent pathways. This improvement is due to the effects of ET in inhibiting inflammation and oxidative stress (APN-dependent) as well as in improving antioxidant enzyme (APN-independent) performance in T2D.

Stem cells possessing the potential to replace damaged myocardium with functional myocytes have drawn increasing attention in the past decade in treating ischemic heart diseases; these diseases are the leading cause of morbidity and mortality in the world. The adult heart has recently been shown to contain a few cardiac stem cells (CSCs) that, in theory, suggest cardiac repair following acute myocardial infarction is possible if the CSC titer could be increased. Stem cell-based therapies, including hematopoietic stem cells and mesenchymal stem cells, were proven to be marginal and transitional. Multiple factors and mechanisms, rather than direct cardiac regeneration are involved in stem cell-mediated cardiac functional improvement. This review will focus on (1) the interaction between inflammation and stem cells; (2) the fate of stem cells at the microcirculatory level, and their subsequent influences on stem cell-based therapies.

Our research focuses on microphysiological aspects of the cardiovascular system, with an emphasis on what is occurring in heart tissues, to learn more about how various diseases arise and how they can be avoided or cured. These diseases include atherosclerosis, diabetes, myocardial infarction, obesity and ischemia/reperfusion (I/R). We use animal models, particularly mice, to aid us in these studies. A key feature of our work centers on dissection of coronary arterioles and examining their functionality using drugs, electrophysiology, fluoroscopy, genomics, proteomics, and standard chemical analyses to determine their physiological status, and compare it with other treated animals. My laboratory is focusing on anti-inflammatory and antioxidative stress therapeutic effects, the roles of sodium salicylate, exercise and resveratrol in type 2 diabetes, I/R injury, obesity, and atherosclerosis. Recently, we began investigations of the effects of stem cells and gastric bypass surgery on vascular dysfunction in obesity and diabetes. Our work identifies how diet,

In addition to its role as a barrier between blood and tissues, the vascular endothelium is responsible for the synthesis and released of a number of vasodilators including prostaglandins, nitric oxide and endothelium-derived hyperpolarizing factor (EDHF). As one of these vasodilators, the specific nature of EDHF has not been fully elucidated, although a number of roles have been proposed. Importantly, many conditions, such as hypertension, hyperlipidemia, heart failure, ischemia-reperfusion and diabetes mellitus comprise vascular endothelial dysfunction with EDHF dysregulation. This article reviews reports on the role of EDHF in diabetes-related endothelial dysfunction.

Excessive oxidative stress and low-grade chronic inflammation are major pathophysiological factors contributing to the development of cardiovascular diseases (CVD) such as hypertension, diabetes and atherosclerosis. Accumulating evidence suggests that a compromised anti-oxidant system can lead to excessive oxidative stress in cardiovascular related organs, resulting in cell damage and death. In addition, increased circulating levels of pro-inflammatory cytokines, such as tumor necrosis factor α, interleukin-6 and C-reactive protein, are closely related to morbidity and mortality of cardiovascular complications. Emerging evidence suggests that interventions including nutrition, pharmacology and exercise may activate expression of cellular anti-oxidant systems via the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 signaling pathway and play a role in preventing inflammatory processes in CVD. The focus of the present review is to summarize recent evidence showing the role of these anti-oxidant and anti-inflammatory interventions in cardiovascular disease. We believe that these findings may prompt new effective pathogenesis-oriented interventions, based on the exercise-induced protection from disease in the cardiovascular system, aimed at targeting oxidant stress and inflammation.

Objective— To verify that adiponectin and tumor necrosis factor (TNF)-α reciprocally regulate their expression, thereby synergistically affecting both coronary and aortic endothelial dysfunction in type 2 diabetic mice. Methods and Results— We examined endothelium-dependent and endothelium-independent vasodilation/vasorelaxation of coronary arterioles and aortas in control mice, diabetic mice (Lepr ^db ), and Lepr ^db treated with adiponectin or neutralizing antibody to TNF-α (anti–TNF-α). Endothelium-dependent vasodilation to acetylcholine in both coronary arterioles and aortas was blunted in Lepr ^db compared with control mice. Endothelium-independent vasodilation to sodium nitroprusside was comparable. Adiponectin and anti–TNF-α improved acetylcholine-induced vasodilation of coronary arterioles and aortas in Lepr ^db without affecting dilator response to sodium nitroprusside. Adiponectin protein expression was significantly reduced, and TNF-α protein expression was significantly greater, in coronary arterioles and aortas of Lepr ^db compared with control mice. Immunofluorescence staining results indicate that adiponectin was colocalized with endothelial cells. Anti–TNF-α treatment upregulated adiponectin protein expression in Lepr ^db coronary arterioles and aortas. Adiponectin administration reduced TNF-α protein expression in Lepr ^db . Although adiponectin receptor 1 protein expression in coronary arterioles and aortas was similar between control and diabetic mice, adiponectin receptor 2 protein expression was significantly reduced in Lepr ^db . Both adiponectin and anti–TNF-α inhibited IκBα phosphorylation and nuclear factor κB protein expression in Lepr ^db , suggesting that adiponectin and TNF-α signaling may converge on nuclear factor κB to reciprocally regulate their expression. Conclusion— A reciprocal suppression occurs between adiponectin and TNF-α that fundamentally affects the regulation of coronary and aortic endothelial function in type 2 diabetic mice.