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Chen C.W.,Beth Israel Deaconess Medical Center | Jaffe I.Z.,Molecular Cardiology Research Institute | Karumanchi S.A.,Beth Israel Deaconess Medical Center | Karumanchi S.A.,Howard Hughes Medical Institute
Cardiovascular Research | Year: 2014

Heart disease is the leading cause of death in women in all countries. A history of pre-eclampsia, one of the most deadly hypertensive complicationsofpregnancy, increases cardiovascular riskbytwotofour times, whichiscomparablewith the risk inducedbysmoking. Substantial epidemiological data reveal that pregnancy-related hypertensive complications are associated with a predisposition to chronic hypertension, premature heart attacks, strokes, and renal complications. Inthis review, we summarize clinical studies that demonstrate this relationship and also discuss the pathogenesis of these long-term complications of pre-eclampsia. Future studies should focus on strategies to prevent the progression of cardiovascular disease in women exposed to pre-eclampsia, thereby improving long-term cardiovascular health in women. © The Author 2014.


Bender S.B.,University of Missouri | Bender S.B.,Diabetes and Cardiovascular Center | McGraw A.P.,Molecular Cardiology Research Institute | Jaffe I.Z.,Molecular Cardiology Research Institute | And 2 more authors.
Diabetes | Year: 2013

Two-thirds of adults in the U.S. are overweight or obese, and another 26 million have type 2 diabetes (T2D). Patients with diabetes and/or the metabolic syndrome have a significantly increased risk of heart attack and stroke compared with people with normal insulin sensitivity. Decreased insulin sensitivity in cardiovascular tissues as well as in traditional targets of insulin metabolic signaling, such as skeletal muscle, is an underlying abnormality in obesity, hypertension, and T2D. In the vasculature, insulin signaling plays a critical role in normal vascular function via endothelial cell nitric oxide production and modulation of Ca2+ handling and sensitivity in vascular smooth muscle cells. Available evidence suggests that impaired vascular insulin sensitivity may be an early, perhaps principal, defect of vascular function and contributor to the pathogenesis of vascular disease in persons with obesity, hypertension, and T2D. In the overweight and obese individual, as well as in persons with hypertension, systemic and vascular insulin resistance often occur in concert with elevations in plasma aldosterone. Indeed, basic and clinical studies have demonstrated that elevated plasma aldosterone levels predict the development of insulin resistance and that aldosterone directly interferes with insulin signaling in vascular tissues. Furthermore, elevated plasma aldosterone levels are associated with increased heart attack and stroke risk. Conversely, renin-angiotensin-aldosterone system and mineralocorticoid receptor (MR) antagonism reduces cardiovascular risk in these patient populations. Recent and accumulating evidence in this area has implicated excessive Ser phosphorylation and proteosomal degradation of the docking protein, insulin receptor substrate, and enhanced signaling through hybrid insulin/IGF-1 receptor as important mechanisms underlying aldosterone-mediated interruption of downstream vascular insulin signaling. Prevention or restoration of these changes via blockade of aldosterone action in the vascular wall with MR antagonists (i.e., spironolactone, eplerenone) may therefore account for the clinical benefit of these compounds in obese and diabetic patients with cardiovascular disease. This review will highlight recent evidence supporting the hypothesis that aldosterone and MR signaling represent an ideal candidate pathway linking early promoters of diabetes, especially overnutrition and obesity, to vascular insulin resistance, dysfunction, and disease. © 2013 by the American Diabetes Association.


Davis B.N.,Tufts University | Davis B.N.,Molecular Cardiology Research Institute | Hilyard A.C.,Molecular Cardiology Research Institute | Nguyen P.H.,Molecular Cardiology Research Institute | And 3 more authors.
Molecular Cell | Year: 2010

The signal transducers of the transforming growth factor β (TGFβ)/bone morphogenetic protein (BMP), the Smads, promote the expression of a subset of miRNAs by facilitating the cleavage reaction by Drosha. The mechanism that limits Smad-mediated processing to a selective group of miRNAs remained hitherto unexplored. In this study, we expand the number of TGFβ/BMP-regulated miRNAs (T/B-miRs) to 20. Of interest, a majority of T/B-miRs contain a consensus sequence (R-SBE) within the stem region of the primary transcripts of T/B-miRs (pri-T/B-miRs). Here, we demonstrate that Smads directly bind the R-SBE. Mutation of the R-SBE abrogates TGFβ/BMP-induced recruitment of Smads, Drosha, and DGCR8 to pri-T/B-miRs and impairs their processing, whereas introduction of R-SBE to unregulated pri-miRNAs is sufficient to recruit Smads and to allow regulation by TGFβ/BMP. Thus, Smads are multifunctional proteins that modulate gene expression transcriptionally through DNA binding and posttranscriptionally through pri-miRNA binding and regulation of miRNA processing. © 2010 Elsevier Inc.


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.


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.


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.


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.


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.


Lavigne P.M.,Molecular Cardiology Research Institute | Karas R.H.,Molecular Cardiology Research Institute
Journal of the American College of Cardiology | Year: 2013

Objectives: This study sought to assess the efficacy of niacin for reducing cardiovascular disease (CVD) events, as indicated by the aggregate body of clinical trial evidence including data from the recently published AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial. Background: Previously available randomized clinical trial data assessing the clinical efficacy of niacin has been challenged by results from AIM-HIGH, which failed to demonstrate a reduction in CVD event incidence in patients with established CVD treated with niacin as an adjunct to intensive simvastatin therapy. Methods: Clinical trials of niacin, alone or combined with other lipid-altering therapy, were identified via MEDLINE. Odds ratios (ORs) for CVD endpoints were calculated with a random-effects meta-analyses. Meta-regression modeled the relationship of differences in on-treatment high-density lipoprotein cholesterol with the magnitude of effect of niacin on CVD events. Results: Eleven eligible trials including 9,959 subjects were identified. Niacin use was associated with a significant reduction in the composite endpoints of any CVD event (OR: 0.66; 95% confidence interval [CI]: 0.49 to 0.89; p = 0.007) and major coronary heart disease event (OR: 0.75; 95% CI: 0.59 to 0.96; p = 0.02). No significant association was observed between niacin therapy and stroke incidence (OR: 0.88; 95% CI: 0.5 to 1.54; p = 0.65). The magnitude of on-treatment high-density lipoprotein cholesterol difference between treatment arms was not significantly associated with the magnitude of the effect of niacin on outcomes. Conclusions: The consensus perspective derived from available clinical data supports that niacin reduces CVD events and, further, that this may occur through a mechanism not reflected by changes in high-density lipoprotein cholesterol concentration. © 2013 American College of Cardiology Foundation.


Ueda K.,Molecular Cardiology Research Institute | Karas R.H.,Molecular Cardiology Research Institute
Steroids | Year: 2013

Estrogen receptors are classically known as ligand-activated transcription factors that regulate gene transcription in cells in response to hormone binding. In addition to this "genomic" signaling pathway, a "rapid, non-nuclear" signaling pathway mediated by cell membrane-associated estrogen receptors also has been recognized. Although for many years there was little evidence to support any physiological relevance of rapid-signaling, very recently evidence has been accumulating supporting the importance of the rapid, non-nuclear signaling as potentially critical for the protective effects of estrogen in the cardiovascular system. Better understanding of the rapid, non-nuclear signaling potentially provides an opportunity to design "pathway-specific" selective estrogen receptor modulators capable of differentially regulating non-nuclear vs. genomic effects that may prove useful ultimately as specific therapies for cardiovascular diseases. © 2012 Elsevier Inc. All rights reserved.

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