Yi Shi

BACKGROUND: Inflammatory mediators that originate in vascular and extravascular tissues promote coronary lesion formation. Adipose tissue may function as an endocrine organ that contributes to an inflammatory burden in patients at risk of cardiovascular complications. In this study, we sought to compare expression of inflammatory mediators in epicardial and subcutaneous adipose stores in patients with critical CAD. METHODS AND RESULTS: Paired samples of epicardial and subcutaneous adipose tissues were harvested at the outset of elective CABG surgery (n=42; age 65+/-10 years). Local expression of chemokine (monocyte chemotactic protein [MCP]-1) and inflammatory cytokines (interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha) was analyzed by TaqMan real-time reverse transcription-polymerase chain reaction (mRNA) and by ELISA (protein release over 3 hours). Significantly higher levels of IL-1beta, IL-6, MCP-1, and TNF-alpha mRNA and protein were observed in epicardial adipose stores. Proinflammatory properties of epicardial adipose tissue were noted irrespective of clinical variables (diabetes, body mass index, and chronic use of statins or ACE inhibitors/angiotensin II receptor blockers) or plasma concentrations of circulating biomarkers. In a subset of samples (n=11), global gene expression was explored by DNA microarray hybridization and confirmed the presence of a broad inflammatory reaction in epicardial adipose tissue in patients with coronary artery disease. The above findings were paralleled by the presence of inflammatory cell infiltrates in epicardial adipose stores. CONCLUSIONS: Epicardial adipose tissue is a source of several inflammatory mediators in high-risk cardiac patients. Plasma inflammatory biomarkers may not adequately reflect local tissue inflammation. Current therapies do not appear to eliminate local inflammatory signals in epicardial adipose tissue.

Endothelial cells, as well as their major products nitric oxide (NO) and prostacyclin, play a key role in the regulation of vascular homeostasis. Diabetes mellitus is an important risk factor for cardiovascular disease. Diabetes-induced endothelial dysfunction is a critical and initiating factor in the genesis of diabetic vascular complications. The present review focuses on both large blood vessels and the microvasculature. The endothelial dysfunction in diabetic macrovascular complications is characterized by reduced NO bioavailability, poorly compensated for by increased production of prostacyclin and/or endothelium-dependent hyperpolarizations, and increased production or action of endothelium-derived vasoconstrictors. The endothelial dysfunction of microvascular complications is primarily characterized by decreased release of NO, enhanced oxidative stress, increased production of inflammatory factors, abnormal angiogenesis, and impaired endothelial repair. In addition, non-coding RNAs (microRNAs) have emerged as participating in numerous cellular processes. Thus, this reviews pays special attention to microRNAs and their modulatory role in diabetes-induced vascular dysfunction. Some therapeutic strategies for preventing and restoring diabetic endothelial dysfunction are also highlighted.

BACKGROUND: The adventitia undergoes remodeling changes after a deep medial coronary injury. Because this process is associated with the formation of adventitial myofibroblasts, which resemble medial smooth muscle (SM) cells, we have examined myofibroblast involvement in the development of neointima. METHODS AND RESULTS: In a porcine model, severe endoluminal coronary injury resulted in fibroblast proliferation and adventitial remodeling. Significant adventitial responses were associated with increased neointimal formation (P < .01). To examine the contribution of adventitial cells to the development of neointima, proliferating cells were labeled with bromodeoxyuridine (BrdU) at 12 and 24 hours after injury, and their subsequent localization was determined by immunohistochemistry (n = 24). At 2 to 3 days after severe injury, the adventitia contained numerous BrdU-labeled cells (37 +/- 4%), whereas the media demonstrated infrequent labeled cells (4 +/- 1%). Adventitial cells lacked alpha-SM actin and desmin, which distinguished them from medial SM cells. At 7 to 8 days, some labeled cells acquired characteristics of myofibroblasts expressing alpha-SM actin. They were found to translocate to the gap between dissected media and contributed to the formation of neointima (76 +/- 19%). At 18 to 35 days, labeled cells were abundant in the neointima (86 +/- 5%). They showed uniform immunostaining for alpha-SM actin but not for desmin, thereby differing from medial SM cells and blood-borne cells. CONCLUSIONS: This study demonstrates translocation of adventitial fibroblasts to neointima, their phenotypic modulation to myofibroblasts, and distinct characteristics of myofibroblasts within neointima after severe endoluminal coronary injury. These findings suggest the significance of vascular fibroblasts in the process of arterial repair.

BACKGROUND: Intraluminal thrombus formation and medial smooth muscle (SM) cell proliferation are recognized responses of the arterial system to injury. In contrast to these well-characterized processes during vascular repair, changes involving the adventitia have been largely neglected in previous studies. Hence, the goal of this investigation was to assess the response of the adventitia to coronary arterial injury. METHODS AND RESULTS: Adventitial changes in porcine coronary arteries subjected to medial injury were characterized by immunohistochemistry, histochemistry, and microscopic morphometry. The rapid development of a hypercellular response in the adventitia was evident 3 days after balloon-induced medial injury. Cell proliferation, as assessed by proliferating cell nuclear antigen immunostaining, reached the maximum level in the adventitia at 3 days, whereas at 14 and 28 days, the number of replicating cells reverted toward the baseline. The proliferating activity in the adventitia exceeded that seen in the media at all times after injury. To further define the changes in the phenotype of adventitial cells, the expression of three cytoskeletal proteins (vimentin, alpha-SM actin, and desmin) was characterized. Fibroblasts in normal adventitia expressed vimentin but no alpha-SM actin or desmin. After injury, these cells acquired characteristics of myofibroblasts expressing alpha-SM actin, which peaked at 7 and 14 days. Desmin expression was patchy in the adventitia, as opposed to its homogeneous distribution in medial SM cells. The modulation of fibroblast phenotype was transient, inasmuch as alpha-SM actin immunostaining declined at 28 days after injury, when dense, collagen-rich scar was evident within the adventitia. The above-described changes involving hypercellularity of the adventitia, myofibroblast formation, and fibrosis were associated with a significant focal adventitial thickening at 3, 7, 14, and 28 days after injury (P < .01 versus uninjured coronary arteries). CONCLUSIONS: This study demonstrates the involvement of the adventitia in the vascular repair process after medial injury. The hypercellularity of the adventitial layer, proliferation of fibroblasts, and modulation of their phenotype to myofibroblasts are associated with the development of the thickened adventitia. It is postulated that these phenomena affect vascular remodeling and may provide an important insight into the mechanisms of vascular disorders.