Consumption of a high-fat/high-fructose Western diet (WD) is linked to rising obesity and heart disease, particularly diastolic dysfunction which characterizes early obesity/metabolic cardiomyopathy. Mounting evidence supports a role for inflammation, oxidative stress and fibrosis in the pathophysiology of metabolic cardiomyopathy. Dipeptidyl peptidase-4 (DPP-4) is a circulating exopeptidase recently reported to be elevated in the plasma of patients with insulin resistance (IR), obesity and heart failure. We hypothesized that a model of WD induced obesity/metabolic cardiomyopathy would exhibit increased DPP-4 activity and cardiac fibrosis with DPP-4 inhibition preventing cardiac fibrosis and the associated diastolic dysfunction.
Four-week-old C57BL6/J mice were fed a high-fat/high-fructose WD with the DPP-4 inhibitor MK0626 for 16 weeks. Cardiac function was examined by high-resolution cine-cardiac magnetic resonance imaging (MRI). Phenotypic analysis included measurements of body and heart weight, systemic IR and DPP-4 activity. Immunohistochemistry and transmission electron microscopy (TEM) were utilized to identify underlying pathologic mechanisms.
We found that chronic WD consumption caused obesity, IR, elevated plasma DPP-4 activity, heart enlargement and diastolic dysfunction. DPP-4 inhibition with MK0626 in WD fed mice resulted in >75% reduction in plasma DPP-4 activity, improved IR and normalized diastolic relaxation. WD consumption induced myocardial oxidant stress and fibrosis with amelioration by MK0626. TEM of hearts from WD fed mice revealed abnormal mitochondrial and perivascular ultrastructure partially corrected by MK0626.
This study provides evidence of a role for increased DPP-4 activity in metabolic cardiomyopathy and a potential role for DPP-4 inhibition in prevention and/or correction of oxidant stress/fibrosis and associated diastolic dysfunction.
DPP-4; oxidative stress; inflammation; heart failure
Population level data support that consumption of fructose and fructose-based sweeteners has dramatically increased and suggest that high dietary intake of fructose is an important factor in the development of the cardiorenal metabolic syndrome (CRS). The CRS is a constellation of cardiac, kidney and metabolic disorders including insulin resistance, obesity, metabolic dyslipidemia, high blood pressure, and evidence of early cardiac and kidney disease. The consequences of fructose metabolism may result in intracellular ATP depletion, increased uric acid production, oxidative stress, inflammation, and increased lipogenesis, which are associated with endothelial dysfunction. Endothelial dysfunction is an early manifestation of vascular disease and a driver for the development of CRS. A better understanding of fructose overconsumption in the development of CRS may provide new insights into pathogenesis and future therapeutic strategies.
Cardiorenal metabolic syndrome; Nitric oxide; Lipogenesis; Insulin resistance; Hypertension; Oxidative stress; Inflammation; Estrogen
Recent data implicate oxidative stress as a mediator of pulmonary hypertension (PH) and of the associated pathological changes to the pulmonary vasculature and right ventricle (RV). Increases in reactive oxygen species (ROS), altered redox state, and elevated oxidant stress have been demonstrated in the lungs and RV of several animal models of PH, including chronic hypoxia, monocrotaline toxicity, caveolin-1 knock-out mouse, and the transgenic Ren2 rat which overexpresses the mouse renin gene. Generation of ROS in these models is derived mostly from the activities of the nicotinamide adenine dinucleotide phosphate oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase. As disease progresses circulating monocytes and bone marrow-derived monocytic progenitor cells are attracted to and accumulate in the pulmonary vasculature. Once established, these inflammatory cells generate ROS and secrete mitogenic and fibrogenic cytokines that induce cell proliferation and fibrosis in the vascular wall resulting in progressive vascular remodeling. Deficiencies in antioxidant enzymes also contribute to pulmonary hypertensive states. Current therapies were developed to improve endothelial function, reduce pulmonary artery pressure, and slow the progression of vascular remodeling in the pulmonary vasculature by targeting deficiencies in either NO (PDE-type 5 inhibition) or PGI2 (prostacyclin analogs), or excessive synthesis of ET-1 (ET receptor blockers) with the intent to improve patient clinical status and survival. New therapies may slow disease progression to some extent, but long term management has not been achieved and mortality is still high. Although little is known concerning the effects of current pulmonary arterial hypertension treatments on RV structure and function, interest in this area is increasing. Development of therapeutic strategies that simultaneously target pathology in the pulmonary vasculature and RV may be beneficial in reducing mortality associated with RV failure.
Pulmonary arterial hypertension; Rosuvastatin; Oxidative stress; Nicotinamide adenine dinucleotide phosphate oxidase; Statins
Two-thirds of adults in the United States are overweight or obese, and another 26 million have type 2 diabetes. Decreased insulin sensitivity in cardiovascular tissue is an underlying abnormality in these individuals. Insulin metabolic signaling increases endothelial cell nitric oxide production. Impaired vascular insulin sensitivity is an early defect leading to impaired vascular relaxation. In overweight and obese persons, as well as in those with hypertension, systemic and vascular insulin resistance often occurs in conjunction with activation of the cardiovascular tissue renin–angiotensin–aldosterone system (RAAS). Activated angiotensin II type 1 receptor and mineralocorticoid receptor signaling promote the development of vascular insulin resistance and impaired endothelial nitric oxide–mediated relaxation. Research in this area has implicated excessive serine phosphorylation and proteasomal degradation of the docking protein insulin receptor substrate and enhanced signaling through hybrid insulin/insulin-like growth factor (IGF-1) receptor as important mechanisms underlying RAAS impediment of downstream vascular insulin metabolic signaling. This review will present recent evidence supporting the notion that RAAS signaling represents a potential pathway for the development of vascular insulin resistance and impaired endothelial-mediated vasodilation.
insulin resistance; endothelium; cardiovascular disease; obesity; nitric oxide
Diabetes; Hypertension; Cardiovascular disease
The obesity epidemic is contributing substantially to the burden of cardiovascular disease including heart disease and congestive heart failure, in the United States and the rest of the world. Overnutrition as a driver of obesity, promotes alterations in fatty acid, lipid, and glucose metabolism that influence myocardial function and progression of heart failure from diastolic to systolic failure. The association of progressive heart failure and progressive chronic kidney disease is well documented and often referred to as the cardiorenal syndrome, as well as a prognosticator for cerebrovascular disease (e.g. stroke). Whether the relationship between obesity, heart disease/failure and risk for chronic kidney disease and stroke is direct or a confluence of risk factors is poorly understood.
Neuroendocrine tumors rarely occur in the cervix or other components of the reproductive system. These tumors have been associated with microsatellite instability, are very aggressive and often associated with poor outcome. Lynch syndrome is an inherited cancer syndrome that has also been associated with microsatellite instability. Here we report a 34-year-old female with Lynch syndrome and a family history of loss of DNA mismatch of the hereditary non-polyposis colorectal cancer repair gene expression who presented with a neuroendocrine tumor of her cervix as the first manifestation of Lynch syndrome. This is the first case reported of a neuroendocrine tumor of the cervix in a patient with Lynch syndrome. We also review the relationship between Lynch Syndrome and neuroendocrine tumors.
neuroendocrine tumors; cervix; Lynch syndrome; gene expression; case report
Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the United States. There was an estimated 7 million cases of diabetic kidney disease (DKD) in the last National Health and Nutrition Examination survey (2005-2008). High blood pressure, hyperglycemia and other metabolic abnormalities interactively promote DKD, thus there has been increasing interest and renewed focus on the metabolic dysregulation and the interactions between heart and kidney pathologies observed in DKD. Indeed metabolic abnormalities that are observed in overweight or obese individuals are known to impact blood pressure regulation in kidney and cardiovascular disease; e.g. cardiorenal metabolic syndrome. In this context, obesity has been associated with increased blood pressure variability and nocturnal non-dipping which are risk predictors for albuminuria and DKD. These collective metabolic abnormalities have also been observed in earlier stages of DKD in association with micro-albuminuria. Herein we review the current literature regarding the role of blood pressure variability and nocturnal non-dipping of blood pressure as well as the presence of DKD, in the absence of albuminuria, as risk predictors for progressive DKD. We also discuss the importance of glycemic and blood pressure control in patients with diabetes and CKD, and the use of oral hypoglycemic agents and anti-hypertensive agents in this patient cohort.
Albuminuria; Proteinuria; Diabetes; Cardiorenal Syndrome; Diabetic Nephropathy; Chronic Kidney Disease; Blood Pressure Variability
Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40-50 years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance are associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contribute to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin-angiotensin-aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance.
Obesity; DPP-4; immunity; uric acid; gender
Thyroid hormones modulate every component of the cardiovascular system necessary for normal cardiovascular development and function. When cardiovascular disease is present, thyroid function tests are characteristically indicated to determine if overt thyroid disorders or even subclinical dysfunction exists. As hypothyroidism, hypertension and cardiovascular disease all increase with advancing age monitoring of TSH, the most sensitive test for hypothyroidism, is important in this expanding segment of our population. A better understanding of the impact of thyroid hormonal status on cardiovascular physiology will enable health care providers to make decisions regarding thyroid hormone evaluation and therapy in concert with evaluating and treating hypertension and cardiovascular disease. The goal of this review is to access contemporary understanding of the effects of thyroid hormones on normal cardiovascular function and the potential role of overt and subclinical hypothyroidism and hyperthyroidism in a variety of cardiovascular diseases.
Thyroid dysfunction; cardiac output; heart failure; peripheral vascular function; atrial fibrillation; coronary artery disease
Hypertension is often associated with increased oxidative stress and systemic insulin resistance. Use of β adrenergic receptor blockers in hypertension is limited due to potential negative influence on insulin sensitivity and glucose homeostasis. We sought to determine the impact of nebivolol, a selective vasodilatory β1adrenergic blocker, on whole-body insulin sensitivity, skeletal muscle oxidative stress, insulin signaling and glucose transport in the transgenic TG(mRen2)27rat (Ren2). This rodent model manifests increased tissue renin angiotensin expression, excess oxidative stress, and whole-body insulin resistance.
Research design and methods
Young (age 6-9 wks) Ren2 and age-matched Sprague-Dawley control rats were treated with nebivolol 10 mg/kg/day or placebo for 21 days. Basal measurements were obtained for glucose and insulin to calculate the Homeostasis Model Assessment (HOMA–IR). Additionally, insulin metabolic signaling, NADPH oxidase activity, reactive oxygen species (ROS), and ultrastructural changes as evaluated by transmission electron microscopy were examined ex vivo in skeletal muscle tissue.
The Ren2 rat demonstrated systemic insulin resistance as examined by HOMA-IR, along with impaired insulin metabolic signaling in skeletal muscle. This was associated with increased oxidative stress and mitochondrial remodeling. Treatment with nebivolol was associated with improvement in insulin resistance and decreased NADPH oxidase activity/levels ROS in skeletal muscle tissue.
Nebivolol treatment for 3 weeks reduces NADPH oxidase activity and improves systemic insulin resistance, in concert with reduced oxidative stress in skeletal muscle in a young rodent model of hypertension, insulin resistance and enhanced tissue RAS expression.
Insulin resistance; oxidative stress; skeletal muscle
Two-thirds of American adults are overweight or obese, 75 million have hypertension and another 25 million have diabetes. Cardiovascular disease is the leading cause of morbidity and mortality and a major driver of health care costs in patients with type 2 diabetes. Observational studies suggest that insulin resistance, hypertension and hyperglycemia independently predict cardiovascular disease and chronic kidney disease. Indeed, coexisting hypertension appears to be a most powerful determinant of cardiovascular disease risk in diabetic patients. This update explores recent investigation which sheds light on our understanding of various metabolic and hemodynamic factors which promote vascular disease, as well as strategies to lessen cardiovascular disease in patients with diabetes.
Obesity has reached epidemic proportions and is a significant public health concern. Obesity is associated with increased diabetes, cardiovascular and kidney disease, and associated morbidity and mortality. Despite the increasing public health problem of obesity, there is a dearth of effective treatment options. Following the FDA mandated withdrawal of sibutramine, the treatment options for obesity were limited to orlistat as the only pharmacological treatment option for long term management of obesity. Recently two new medications (Belviq and Qsymia) were approved by FDA for long term management of obesity. Many other anti-obesity drugs are under development. Bariatric surgery has been shown to be effective in the treatment of obesity and its comorbidities. The available data suggests that even modest weight loss improves diabetes and cardiovascular disease (CVD) risk factors. We summarize the treatment options for obesity and the efficacy of these options in ameliorating cardiovascular risk factors. We also focus on the recently approved anti-obesity drugs.
Diabetes mellitus type 2 (T2DM) is a widespread chronic medical condition with prevalence bordering on the verge of an epidemic. It is of great concern that cardiovascular disease is more common in patients with diabetes than the non-diabetic population. While hypertensive and ischemic heart disease is more common in diabetic patients, there is another type of heart disease in diabetes that is not associated with hypertension or coronary artery disease. This muscle functional disorder is termed “diabetic cardiomyopathy”. Diastolic dysfunction characterized by impaired diastolic relaxation time and reduced contractility precedes systolic dysfunction and is the main pathogenic hallmark of this condition. Even though the pathogenesis of “diabetic cardiomyopathy” is still controversial, impaired cardiac insulin sensitivity and metabolic overload are emerging as major molecular and metabolic mechanisms for cardiac dysfunction. Systemic insulin resistance, hyperinsulinemia, dysregulation of adipokine secretion, increases in circulating levels of inflammatory mediators, aberrant activation of renin angiotensin aldosterone system (RAAS), and increased oxidative stress contribute dysregulated insulin and metabolic signaling in the heart and development of diastolic dysfunction. In addition, maladaptive calcium homeostasis and endothelial cell dysregulation endoplasmic reticular stress play a potential role in cardiomyocyte fibrosis/diastolic dysfunction. In this review, we will focus on emerging molecular and metabolic pathways underlying cardiac dysfunction in diabetes. Elucidation of these mechanisms should provide a better understanding of the various cardiac abnormalities associated with diastolic dysfunction and its progression to systolic dysfunction and heart failure.
Diabetes; RAAS; Cardiac Dysfunction; Cardiorenal Metabolic syndrome; Diabetic Cardiomyopathy; Insulin Resistance
Insulin resistance is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular diseases. Insulin exerts pro- and anti-atherogenic actions on the vasculature. The balance between nitric oxide (NO)-dependent vasodilator actions and endothelin-1- dependent vasoconstrictor actions of insulin is regulated by phosphatidylinositol 3-kinase-dependent (PI3K) - and mitogen-activated protein kinase (MAPK)-dependent signaling in vascular endothelium, respectively. During insulin-resistant conditions, pathway-specific impairment in PI3K-dependent signaling may cause imbalance between production of NO and secretion of endothelin-1 and lead to endothelial dysfunction. Insulin sensitizers that target pathway-selective impairment in insulin signaling are known to improve endothelial dysfunction. In this review, we discuss the cellular mechanisms in the endothelium underlying vascular actions of insulin, the role of insulin resistance in mediating endothelial dysfunction, and the effect of insulin sensitizers in restoring the balance in pro- and anti-atherogenic actions of insulin.
Nitric Oxide; Insulin Resistance; Endothelial Dysfunction; Metabolic Syndrome
Excessive activation of gelatinases (MMP-2/-9) is a key cause of detrimental outcomes in neurodegenerative diseases. A single-dimension zymography has been widely used to determine gelatinase expression and activity, but this method is inadequate in resolving complex enzyme isoforms, because gelatinase expression and activity could be modified at transcriptional and posttranslational levels. In this study, we investigated gelatinase isoforms under in vitro and in vivo conditions using two-dimensional (2D) gelatin zymography electrophoresis, a protocol allowing separation of proteins based on isoelectric points (pI) and molecular weights. We observed organomercuric chemical 4-aminophenylmercuric acetate-induced activation of MMP-2 isoforms with variant pI values in the conditioned medium of human fibrosarcoma HT1080 cells. Studies with murine BV-2 microglial cells indicated a series of proform MMP-9 spots separated by variant pI values due to stimulation with lipopolysaccharide (LPS). The MMP-9 pI values were shifted after treatment with alkaline phosphatase, suggesting presence of phosphorylated isoforms due to the proinflammatory stimulation. Similar MMP-9 isoforms with variant pI values in the same molecular weight were also found in mouse brains after ischemic and traumatic brain injuries. In contrast, there was no detectable pI differentiation of MMP-9 in the brains of chronic Zucker obese rats. These results demonstrated effective use of 2D zymography to separate modified MMP isoforms with variant pI values and to detect posttranslational modifications under different pathological conditions.
Obesity-related glomerulopathy is characterized initially by glomerular hyperfiltration with hypertrophy and then development of proteinuria. Putative mechanisms include endothelial dysfunction and filtration barrier injury due to oxidant stress and immune activation. There has been recent interest in targeting dipeptidyl peptidase 4 (DPP4) enzyme due to increasing role in non-enzymatic cellular processes.
We utilized the Zucker obese (ZO) rat, (aged 8 weeks) fed a normal chow or diet containing the DPP4 inhibitor linagliptin for 8 weeks (83mg/kg rat chow).
Compared to lean controls, there were increases in plasma DPP4 activity along with proteinuria in ZO rats. ZO rats further displayed increases in glomerular size and podocyte foot process effacement. These findings occurred in parallel with decreased endothelial stromal-derived factor-1α (SDF-1α), increased oxidant markers, and tyrosine phosphorylation of nephrin and serine phosphorylation of the mammalian target of rapamycin (mTOR). DPP4 inhibition improved proteinuria along with filtration barrier remodeling, circulating and kidney tissue DPP4 activity, increased active glucagon like peptide–1 (GLP-1) as well as SDF-1α, and improved oxidant markers and the podocyte-specific protein nephrin.
These data support a role for DPP4 in glomerular filtration function and targeting DPP4 with inhibition improves oxidant stress-related glomerulopathy and associated proteinuria.
SDF-1α; linagliptin; NADPH oxidase; DPP4 activity; obesity
Insulin resistance and associated reductions in cardiac insulin metabolic signaling is emerging as a major factor for the development of heart failure and assumes more importance because of an epidemic increase in obesity and the cardiorenal metabolic syndrome and our aging population. Major factors contributing to the development of cardiac insulin resistance are oxidative stress, hyperglycemia, hyperlipidemia, dysregulated secretion of adipokines/cytokines and inappropriate activation of renin-angiotensin II-aldosterone system (RAAS) and the sympathetic nervous system. The effects of cardiac insulin resistance are exacerbated by metabolic, endocrine and cytokine alterations associated with systemic insulin resistance. The aggregate of these various alterations leads to an insulin resistant phenotype with metabolic inflexibility, impaired calcium handling, mitochondrial dysfunction and oxidative stress, dysregulated myocardial-endothelial interactions resulting in energy deficiency, impaired diastolic dysfunction, myocardial cell death and cardiac fibrosis. Therefore, understanding the molecular mechanisms linking insulin resistance and heart failure may help to design new and more effective mechanism-based drugs to improve myocardial and systemic insulin resistance.
Cardiac insulin resistance; cardiorenal metabolic syndrome
A recent study reports that the combination of an angiotensin-receptor blocker (ARB) and a calcium-channel blocker (versus a high-dose ARB) is associated with improved blood pressure control and reduced cardiovascular, cerebrovascular and heart failure events in an elderly chronic kidney disease population. This finding raises the possibility of using fixed-dose drug combinations to improve efficacy and compliance of antihypertensive medications.
Cardiovascular disease, which accounts for the highest morbidity and mortality in the United States, has several major risk factors, including aging and diabetes. Overweight and obesity, especially abdominal obesity, have been increasingly implicated as independent risk factors in the development of cardiovascular disease. Metabolic and/or diabetic cardiomyopathy has been especially associated with excess body weight caused by chronic over-nutrition and high-fat feeding. In the initial stages, obesity is now understood to cause significant dysregulation of cardiac fatty acid and glucose metabolism. These abnormalities are due, in part, to increased oxidative stress, which in turn can cause deleterious effects on intracellular signaling pathways that control cellular growth and proliferation. This increase in oxidative stress is coupled with reduced anti-oxidant species and dysregulation of metabolic signaling pathways. The cardiomyopathy seen with obesity is associated with increased interstitial fibrosis and diastolic dysfunction. Over time, evolving abnormalities include hypertrophy and systolic dysfunction, eventually leading to heart failure.
insulin; metabolic; signaling; heart