Mechanisms of Comorbidities Associated With the Metabolic Syndrome: Insights from the JCR:LA-cp Corpulent Rat Strain

Obesity and its metabolic complications have emerged as the epidemic of the new millennia. The use of obese rodent models continues to be a productive component of efforts to understand the concomitant metabolic complications of this disease. In 1978, the JCR:LA-cp rat model was developed with an autosomal recessive corpulent (cp) trait resulting from a premature stop codon in the extracellular domain of the leptin receptor. Rats that are heterozygous for the cp trait are lean-prone, while those that are homozygous (cp/cp) spontaneously display the pathophysiology of obesity as well as a metabolic syndrome (MetS)-like phenotype. Over the years, there have been formidable scientific contributions that have originated from this rat model, much of which has been reviewed extensively up to 2008. The premise of these earlier studies focused on characterizing the pathophysiology of MetS-like phenotype that was spontaneously apparent in this model. The purpose of this review is to highlight areas of recent advancement made possible by this model including; emerging appreciation of the thrifty gene hypothesis in the context of obesity, the concept of how chronic inflammation may drive obesogenesis, the impact of acute forms of inflammation to the brain and periphery during chronic obesity, the role of dysfunctional insulin metabolism on lipid metabolism and vascular damage, and the mechanistic basis for altered vascular function as well as novel parallels between the human condition and the female JCR:LA-cp rat as a model for polycystic ovary disease (PCOS)

Comparison of Cardiovascular Benefits of Bariatric Surgery and Abdominal Lipectomy

PURPOSE OF REVIEW: The purpose of this review is to examine recent evidence supporting effectiveness of bariatric surgery and abdominal lipectomy as interventional strategies aimed at reduction in incidence of cardiovascular disease (CVD) and related morbidity and mortality in obese and metabolic syndrome patients. RECENT FINDINGS: While several studies show reduction in CVD risk factors in patients who have undergone both the Roux-en-Y gastric bypass and sleeve gastrectomy, very few demonstrate actual improvements in cardiovascular function, or a decrease in CVD events or CVD-related mortality. Consequently, the cardiovascular benefits of the less invasive sleeve gastrectomy in comparison to the gastric bypass are also unclear. Striking new data on large patient samples demonstrate significant positive correlation between gastric bypass and CVD risk factor reduction only in patients who are diabetic or \u3e 50 years of age at the time of surgery, with no significant differences in non-diabetic and younger patients and with significant side effects. On the other hand, a markedly less invasive removal of abdominal subcutaneous adipose tissue via lipectomy consistently and significantly improved CVD risk factors as well as cardiovascular function in the very few studies available. Overall, neither the potential nor the definitive cardiovascular benefits of either of the commonly used bariatric surgical or the various lipectomy procedures have been adequately explored. Future basic science and clinical studies have the opportunity to understand the mechanisms and long-term consequences of both approaches and develop personalized approaches with higher benefit to side effect ratios

Can microRNAs Be Biomarkers or Targets for Therapy of Ischemic Coronary Artery Disease in Metabolic Syndrome?

Due to their exceptional stability in the circulation, microRNAs (miRs) are being identified as promising biomarkers. On the other hand, their propensity to regulate networks of functionally closely related genes and relative ease of delivery makes them attractive targets for therapy. However, neither application is without challenges, especially as it applies to ischemic coronary artery disease (CAD). This review: 1) describes miRs which have been most consistently found to be associated with the most common manifestations of CAD, including atherosclerosis, angina pectoris, myocardial infarction and myocardial reperfusion through arteriogenesis, 2) emphasizes those miRs which are also altered in metabolic syndrome and its component pathologies, 3) discusses challenges which currently prevent clinical application related to inconsistencies between findings in cell culture, animal models and among human studies, as well as technical challenges, and 4) offers some suggestions towards resolutions of these discrepancies

The Metabolic Syndrome, Oxidative Stress, Environment, and Cardiovascular Disease: The Great Exploration

The metabolic syndrome affects 30% of the US population with increasing prevalence. In this paper, we explore the relationship between the metabolic syndrome and the incidence and severity of cardiovascular disease in general and coronary artery disease (CAD) in particular. Furthermore, we look at the impact of metabolic syndrome on outcomes of coronary revascularization therapies including CABG, PTCA, and coronary collateral development. We also examine the association between the metabolic syndrome and its individual component pathologies and oxidative stress. Related, we explore the interaction between the main external sources of oxidative stress, cigarette smoke and air pollution, and metabolic syndrome and the effect of this interaction on CAD. We discuss the apparent lack of positive effect of antioxidants on cardiovascular outcomes in large clinical trials with emphasis on some of the limitations of these trials. Finally, we present evidence for successful use of antioxidant properties of pharmacological agents, including metformin, statins, angiotensin II type I receptor blockers (ARBs), and angiotensin II converting enzyme (ACE) inhibitors, for prevention and treatment of the cardiovascular complications of the metabolic syndrome

20-HETE in the Regulation of Vascular and Cardiac Function

20-HETE, the omega-hydroxylation product of arachidonic acid catalyzed by enzymes of the cytochrome P450 (CYP) 4A and 4F gene families, is a bioactive lipid mediator with potent effects on the vasculature including stimulation of smooth muscle cell contractility, migration and proliferation as well as activation of endothelial cell dysfunction and inflammation. Clinical studies have shown elevated levels of plasma and urinary 20-HETE in human diseases and conditions such as hypertension, obesity and metabolic syndrome, myocardial infarction, stroke, and chronic kidney diseases. Studies of polymorphic associations also suggest an important role for 20-HETE in hypertension, stroke and myocardial infarction. Animal models of increased 20-HETE production are hypertensive and are more susceptible to cardiovascular injury. The current review summarizes recent findings that focus on the role of 20-HETE in the regulation of vascular and cardiac function and its contribution to the pathology of vascular and cardiac diseases

Role of MMP2 and MMP9 in TRPV4-Induced Lung Injury

Ca(2+) entry through transient receptor potential vanilloid 4 (TRPV4) results in swelling, blebbing, and detachment of the epithelium and capillary endothelium in the intact lung. Subsequently, increased permeability of the septal barrier and alveolar flooding ensue. In this study, we tested the hypothesis that TRPV4 activation provides a Ca(2+) source necessary for proteolytic disruption of cell-cell or cell-matrix adhesion by matrix metalloproteinases (MMPs) 2 and 9, thus increasing septal barrier permeability. In our study, C57BL/6 or TRPV4(-/-) mouse lungs were perfused with varying doses of the TRPV4 agonist GSK-1016790A (Sigma) and then prepared for Western blot. Lung injury, assessed by increases in lung wet-to-dry weight ratios and total protein levels in the bronchoalveolar lavage fluid, was increased in a dose-dependent fashion in TRPV4(+/+) but not TRPV4(-/-) lungs. In concert with lung injury, we detected increased active MMP2 and MMP9 isoforms, suggesting that TRPV4 can provide the Ca(2+) source necessary for increased MMP2/9 activation. Furthermore, tissue inhibitor of metalloproteinases (TIMP) 2 levels in the TRPV4-injured lungs were decreased, suggesting that TRPV4 activation increases the availability of these active MMPs. We then determined whether MMP2 and MMP9 mediate TRPV4-induced lung injury. Pharmacological blockade (SB-3CT, 1 μM; Sigma) of MMP2 and MMP9 resulted in protection against TRPV4-induced lung injury. We conclude that TRPV4 activation and the subsequent Ca(2+) transient initiates a rapid cascade of events leading to release and activation of the gelatinase MMPs, which then contribute to lung injury