Entity

Time filter

Source Type

Boston, MA, United States

McGraw A.P.,Molecular Cardiology Research Institute
Journal of the American Heart Association | Year: 2013

Aldosterone levels correlate with the incidence of myocardial infarction and mortality in cardiovascular patients. Aldosterone promotes atherosclerosis in animal models, but the mechanisms are poorly understood. Aldosterone was infused to achieve pathologically relevant levels that did not increase blood pressure in the atherosclerosis-prone apolipoprotein E-knockout mouse (ApoE-/-). Aldosterone increased atherosclerosis in the aortic root 1.8±0.1-fold after 4 weeks and in the aortic arch 3.7±0.2-fold after 8 weeks, without significantly affecting plaque size in the abdominal aorta or traditional cardiac risk factors. Aldosterone treatment increased lipid content of plaques (2.1±0.2-fold) and inflammatory cell content (2.2±0.3-fold), induced early T-cell (2.9±0.3-fold) and monocyte (2.3±0.3-fold) infiltration into atherosclerosis-prone vascular regions, and enhanced systemic inflammation with increased spleen weight (1.52±0.06-fold) and the circulating cytokine RANTES (regulated and normal T cell secreted; 1.6±0.1-fold). To explore the mechanism, 7 genes were examined for aldosterone regulation in the ApoE-/- aorta. Further studies focused on the proinflammatory placental growth factor (PlGF), which was released from aldosterone-treated ApoE-/- vessels. Activation of the mineralocorticoid receptor by aldosterone in human coronary artery smooth muscle cells (SMCs) caused the release of factors that promote monocyte chemotaxis, which was inhibited by blocking monocyte PlGF receptors. Furthermore, PlGF-deficient ApoE-/- mice were resistant to early aldosterone-induced increases in plaque burden and inflammation. Aldosterone increases early atherosclerosis in regions of turbulent blood flow and promotes an inflammatory plaque phenotype that is associated with rupture in humans. The mechanism may involve SMC release of soluble factors that recruit activated leukocytes to the vessel wall via PlGF signaling. These findings identify a novel mechanism and potential treatment target for aldosterone-induced ischemia in humans. Source


Koenig J.B.,Tufts University | Jaffe I.Z.,Tufts University | Jaffe I.Z.,Molecular Cardiology Research Institute
Current Hypertension Reports | Year: 2014

The mineralocorticoid receptor (MR) is a key regulator of blood pressure. MR antagonist drugs are used to treat hypertension and heart failure, resulting in decreased mortality by mechanisms that are not completely understood. In addition to the kidney, MR is also expressed in the smooth muscle cells (SMCs) of the vasculature, where it is activated by the hormone aldosterone and affects the expression of genes involved in vascular function at the cellular and systemic levels. Following vascular injury due to mechanical or physiological stresses, vessels undergo remodeling resulting in SMC hypertrophy, migration, and proliferation, as well as vessel fibrosis. Exuberant vascular remodeling is associated with poor outcomes in cardiovascular patients. This review compiles recent findings on the specific role of SMC-MR in the vascular remodeling process. The development and characterization of a SMC-specific MR-knockout mouse has demonstrated a direct role for SMC-MR in vascular remodeling. Additionally, several novel mechanisms contributing to SMC-MR-mediated vascular remodeling have been identified and are reviewed here, including Rho-kinase signaling, placental growth factor signaling through vascular endothelial growth factor type 1 receptor, and galectin signaling. © 2014 Springer Science+Business Media. Source


McCurley A.,Molecular Cardiology Research Institute | Jaffe I.Z.,Molecular Cardiology Research Institute | Jaffe I.Z.,Tufts Medical Center
Molecular and Cellular Endocrinology | Year: 2012

The mineralocorticoid receptor (MR), a member of the steroid receptor family, regulates blood pressure by mediating the effects of the hormone aldosterone (Aldo) on renal sodium handling. Over the past decade, it has become clear that MR is expressed in the cardiovascular system and interest has grown in understanding the direct role of the MR in regulating vascular function and contributing to cardiovascular disease. This interest stems from multiple clinical studies in which drugs that decrease MR activation also reduce the incidence of heart attacks, strokes, and mortality out of proportion to modest changes in systemic blood pressure. The presence of functional mineralocorticoid receptors in vascular smooth muscle and endothelial cells is now well established and, while still controversial, data supports the vasculature as an Aldo-responsive tissue. This review summarizes recent advances in our understanding of the role of vascular MR in regulating normal vascular function and in promoting vascular disease. In vitro data, in vivo animal studies, and human data are reviewed suggesting a role for MR-activation in promoting vascular oxidative stress, inhibiting vascular relaxation, and contributing to vessel inflammation, fibrosis, and remodeling. These detrimental vascular effects of MR activation appear to be independent of changes in blood pressure and are synergistic with the presence of endothelial dysfunction or damage. Thus, in humans with underlying cardiovascular disease or cardiovascular risk factors, vascular MR activation may promote vascular aging and atherosclerosis thereby contributing to the pathophysiology of heart attack, stroke, and possibly even hypertension. Further exploration of the molecular mechanisms for the detrimental vascular effects of MR activation has the potential to identify novel therapeutic targets to prevent or treat common cardiovascular disorders. © 2011 Elsevier Ireland Ltd. Source


Jafri H.,Molecular Cardiology Research Institute | Alsheikh-Ali A.A.,Tufts University | Alsheikh-Ali A.A.,Institute of Cardiac science | Karas R.H.,Molecular Cardiology Research Institute
Journal of the American College of Cardiology | Year: 2010

Objectives: We sought to examine the relationship between high-density lipoprotein cholesterol (HDL-C) levels and the risk of the development of cancer in large randomized controlled trials (RCTs) of lipid-altering interventions. Background: Epidemiologic data demonstrate an inverse relationship between serum total cholesterol levels and incident cancer. We recently reported that lower levels of low-density lipoprotein cholesterol are associated with a significantly higher risk of incident cancer in a meta-analysis of large RCTs of statin therapy. However, little is known about the relationship between HDL-C levels and cancer risk. Methods: A systematic MEDLINE search identified lipid intervention RCTs with ≥1,000 person-years of follow-up, providing baseline HDL-C levels and rates of incident cancer. Using random-effects meta-regressions, we evaluated the relationship between baseline HDL-C and incident cancer in each RCT arm. Results: A total of 24 eligible RCTs were identified (28 pharmacologic intervention arms and 23 control arms), with 625,477 person-years of follow-up and 8,185 incident cancers. There was a significant inverse association between baseline HDL-C levels and the rate of incident cancer (p = 0.018). The inverse association persisted after adjusting for baseline low-density lipoprotein cholesterol, age, body mass index (BMI), diabetes, sex, and smoking status, such that for every 10-mg/dl increment in HDL-C, there was a 36% (95% confidence interval: 24% to 47%) relatively lower rate of the development of cancer (p < 0.001). Conclusions: There is a significant inverse association between HDL-C and the risk of incident cancer that is independent of LDL-C, age, BMI, diabetes, sex, and smoking. © 2010 American College of Cardiology Foundation. Source


Jafri H.,Molecular Cardiology Research Institute | Alsheikh-Ali A.A.,Institute of Cardiac science | Karas R.H.,Molecular Cardiology Research Institute
Annals of Internal Medicine | Year: 2010

Background: Low levels of high-density lipoprotein cholesterol (HDL-C) are associated with an increased risk for myocardial infarction (MI). Although statins reduce the risk for MI, most cardiovascular events still occur despite statin treatment. Purpose: Using meta-analysis of large randomized, controlled trials (RCTs) of statins to determine whether statins alter the relationship between HDL-C level and MI. Data Sources: MEDLINE search to February 2010, ClinicalTrials.gov, and reference lists from eligible studies. Study Selection: English-language RCTs of statin-treated patients versus control participants with 1000 or more person-years of follow-up and reported HDL-C levels and MI. Data Extraction: Two independent investigators extracted data from eligible RCTs. Data Synthesis: Twenty eligible RCTs were identified (543 210 person-years of follow-up and 7838 MIs). After adjustment for on-treatment LDL-C levels, age, hypertension, diabetes, and tobacco use, there was a significant inverse association between HDL-C levels and risk for MI in statin-treated patients and control participants. In Poisson meta-regressions, every 0.26-mmol/L (10-mg/dL) decrease in HDL-C was associated with 7.1 (95% CI, 6.8 to 7.3) and 8.3 (CI, 8.1 to 8.5) more MIs per 1000 person-years in statin-treated patients and control participants, respectively. The inverse association between HDL-C levels and MI did not differ between statin-treated patients and control participants (P = 0.57). Limitation: The observed associations may be explained by unmeasured confounding and do not imply causality in the relationship between HDL-C level and cardiovascular risk. Conclusion: Statins do not alter the relationship between HDL-C level and cardiovascular risk, such that low levels of HDL-C remain significantly and independently associated with increased risk despite statin treatment. The remaining risk seen in statin-treated patients may be partly explained by low HDL-C levels or other factors associated with low levels of HDL-C. Primary Funding Source: None © 2010 American College of Physicians. Source

Discover hidden collaborations