Pregestational type 2 diabetes mellitus induces cardiac hypertrophy in the murine embryo through cardiac remodeling and fibrosis

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d7379819e147">Background</h5> <p id="P2">Cardiac hypertrophy is highly prevalent in patients with type 2 diabetes mellitus (T2DM). Experimental evidence has implied that pregnant women with T2DM and their children are at an increased risk of cardiovascular diseases. Our previous mouse model study has revealed that maternal T2DM induces structural heart defects in their offspring. </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d7379819e152">Objective</h5> <p id="P3">The present study aims to determine whether maternal T2DM induces embryonic heart hypertrophy in a murine model of diabetic embryopathy. </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d7379819e157">Study design</h5> <p id="P4">The T2DM embryopathy model was established by feeding 4-week-old female C57BL/6J mice with a high-fat diet (HFD) for 15 weeks. Cardiac hypertrophy in embryos at embryonic day 17.5 was characterized by measuring heart size and thickness of the right and left ventricle walls and the interventricular septum, as well as the expression of β-myosin heavy chain (β-MHC), atrial natriuretic peptide (ANP), insulin-like growth factor 1 (IGF1), desmin (DES), and adrenomedullin (ADM). Cardiac remodeling was determined by collagen synthesis and fibronectin synthesis. Fibrosis was evaluated by Masson staining and determining the expression of connective tissue growth factor (CTGF), osteopontin (OPN), and Galectin 3 (GAL3) genes. Cell apoptosis also was measured in the developing heart. </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d7379819e162">Results</h5> <p id="P5">The thicknesses of the left ventricle walls and the interventricular septum of embryonic hearts exposed to maternal diabetes were significantly thicker than those in the nondiabetic (ND) group. Maternal diabetes significantly increased β-MHC, ANP, IGF1 and DES expression, but decreased expression of ADM. Moreover, collagen synthesis was significantly elevated, whereas fibronectin synthesis was suppressed, in embryonic hearts from diabetic dams, suggesting that cardiac remodeling is a contributing factor to cardiac hypertrophy. The cardiac fibrosis marker, GAL3, was induced by maternal diabetes. Furthermore, maternal T2DM activated the pro-apoptotic c-Jun-N-terminal kinase (JNK1/2) stress signaling and triggered cell apoptosis by increasing the number of TUNEL positive cells (10.4 ± 2.2% of the T2DM group vs. 3.8 ± 0.7% of the ND group, <i>P</i> < 0.05). </p> </div><div class="section"> <a class="named-anchor" id="S5">  </a> <h5 class="section-title" id="d7379819e170">Conclusions</h5> <p id="P6">Maternal T2DM induces cardiac hypertrophy in embryonic hearts. Adverse cardiac remodeling, including elevated collagen synthesis, suppressed fibronectin synthesis, profibrosis and apoptosis, is implicated as the etiology of cardiac hypertrophy. </p> </div>

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D Dhanasekaran, E Reddy (2008)

Jun N-terminal kinases or JNKs play a critical role in death receptor-initiated extrinsic as well as mitochondrial intrinsic apoptotic pathways. JNKs activate apoptotic signaling by the upregulation of pro-apoptotic genes through the transactivation of specific transcription factors or by directly modulating the activities of mitochondrial pro- and antiapoptotic proteins through distinct phosphorylation events. This review analyses our present understanding of the role of JNK in apoptotic signaling and the various mechanisms by which JNK promotes apoptosis.

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Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease.

Sarka Lisonkova, K Joseph (2013)

The population-based incidence of early-onset (<34 weeks) and late-onset preeclampsia (≥34 weeks) has not been adequately studied. We examined the gestational age-specific incidence of preeclampsia onset and identified the associated risk factors and birth outcomes. All singleton deliveries in Washington State, 2003-2008 (n = 456,668), were included, and preeclampsia onset was determined from hospital records linked to birth certificates. Cox and logistic regression models were used to obtain adjusted hazard ratios and odds ratios (AORs) for risk factors and birth outcomes, respectively. The overall preeclampsia rate was 3.1% and the incidence increased sharply with gestation; early- and late-onset preeclampsia rates were 0.38% and 2.72%, respectively. Among women with early-onset preeclampsia, 12% delivered at a gestation of 34 weeks or longer. Risk/protective factors common to both diseases included older maternal age, Hispanic and Native-American race, smoking, unmarried status, and male fetus. African-American race, chronic hypertension, and congenital anomalies were more strongly associated with early-onset preeclampsia, whereas younger maternal age, nulliparity, and diabetes mellitus were more strongly associated with late-onset disease. Early- but not late-onset preeclampsia conferred a high risk of fetal death (AOR, 5.8; 95% confidence interval [CI], 4.0-8.3 vs AOR, 1.3; 95% CI, 0.8-2.0, respectively). The AOR for perinatal death/severe neonatal morbidity was 16.4 (95% CI, 14.5-18.6) in early-onset and 2.0 (95% CI, 1.8-2.3) in late-onset preeclampsia. Early- and late-onset preeclampsia shares some etiological features, differ with regard to several risk factors, and lead to different outcomes. The 2 preeclampsia types should be treated as distinct entities from an etiological and prognostic standpoint. Copyright © 2013 Mosby, Inc. All rights reserved.

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Mitogen-activated protein kinase signaling in the heart: angels versus demons in a heart-breaking tale.

Beth A. Rose, Thomas I Force, Yibin Wang (2010)

Among the myriad of intracellular signaling networks that govern the cardiac development and pathogenesis, mitogen-activated protein kinases (MAPKs) are prominent players that have been the focus of extensive investigations in the past decades. The four best characterized MAPK subfamilies, ERK1/2, JNK, p38, and ERK5, are the targets of pharmacological and genetic manipulations to uncover their roles in cardiac development, function, and diseases. However, information reported in the literature from these efforts has not yet resulted in a clear view about the roles of specific MAPK pathways in heart. Rather, controversies from contradictive results have led to a perception that MAPKs are ambiguous characters in heart with both protective and detrimental effects. The primary object of this review is to provide a comprehensive overview of the current progress, in an effort to highlight the areas where consensus is established verses the ones where controversy remains. MAPKs in cardiac development, cardiac hypertrophy, ischemia/reperfusion injury, and pathological remodeling are the main focuses of this review as these represent the most critical issues for evaluating MAPKs as viable targets of therapeutic development. The studies presented in this review will help to reveal the major challenges in the field and the limitations of current approaches and point to a critical need in future studies to gain better understanding of the fundamental mechanisms of MAPK function and regulation in the heart.