Embryonic and foetal development are critical periods of development in which several environmental cues determine health and disease in adulthood. Maternal conditions and an unfavourable intrauterine environment impact foetal development and may programme the offspring for increased predisposition to metabolic diseases and other chronic pathologic conditions throughout adult life. Previously, non-communicable chronic diseases were only associated with genetics and lifestyle. Now the origins of non-communicable chronic diseases are associated with earlylife adaptations that produce long-term dysfunction. Early-life environment sets the long-term health and disease risk and can span through multiple generations. Recent research in developmental programming aims at identifying the molecular mechanisms responsible for developmental programming outcomes that impact cellular physiology and trigger adulthood disease. The identification of new therapeutic targets can improve offspring's health management and prevent or overcome adverse consequences of foetal programming. This review summarizes recent biomedical discoveries in the Developmental Origins of Health and Disease (DOHaD) hypothesis and highlight possible developmental programming mechanisms, including prenatal structural defects, metabolic (mitochondrial dysfunction, oxidative stress, protein modification), epigenetic and glucocorticoid signalling-related mechanisms suggesting molecular clues for the causes and consequences of programming of increased susceptibility of offspring to metabolic disease after birth. Identifying mechanisms involved in DOHaD can contribute to early interventions in pregnancy or 2 of 21 | GRILO et aL.

No abstract

Cardiovascular disease (CVD) is the biggest killer worldwide, composing a major economic burden for health care systems. Obesity and diabetes are dual epidemics on the rise and major risk factors predisposing for CVD. Increased obesity‐ and diabetes‐related incidence is now observed among children, adolescents, and young adults. Gestational diabetes mellitus (GDM) is the most common metabolic pregnancy disorder, and its prevalence is rapidly increasing. During pregnancies complicated by GDM, the offspring are exposed to a compromised intrauterine environment characterized by hyperglycemic periods. Unfavorable in utero conditions at critical periods of fetal cardiac development can produce developmental adaptations that remodel the cardiovascular system in a way that can contribute to adult‐onset of heart disease due to the programming during fetal life. Epidemiological studies have reported increased cardiovascular complications among GDM‐descendants, highlighting the urgent need to investigate and understand the mechanisms modulated during fetal development of in utero GDM‐exposed offspring that predispose an individual to increased CVD during life. In this manuscript, we overview previous studies in this area and gather evidence linking GDM and CVD development in the offspring, providing new insights on novel mechanisms contributing to offspring CVD programming by GDM, from the role of maternal–fetal interactions to their impact on fetal cardiovascular development, how the perpetuation of cardiac programming is maintained in postnatal life, and advance the intergenerational implications contributing to increased CVD premature origin. Understanding the perpetuation of CVD can be the first step to manage and reverse this leading cause of morbidity and mortality. This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology Cardiovascular Diseases > Molecular and Cellular Physiology Metabolic Diseases > Genetics/Genomics/Epigenetics

Background: Cardiovascular diseases (CVDs) are a leading risk factor for mortality worldwide and the number of CVDs victims is predicted to rise through 2030. While several external parameters (genetic, behavioral, environmental and physiological) contribute to cardiovascular morbidity and mortality; intrinsic metabolic and functional determinants such as insulin resistance, hyperglycemia, inflammation, high blood pressure and dyslipidemia are considered to be dominant factors. Methods: Pubmed searches were performed using different keywords related with mitochondria and cardiovascular disease and risk. In vitro, animal and human results were extracted from the hits obtained. Results: High cardiac energy demand is sustained by mitochondrial ATP production, and abnormal mitochondrial function has been associated with several lifestyle- and aging-related pathologies in the developed world such as diabetes, non-alcoholic fatty liver disease (NAFLD) and kidney diseases, that in turn can lead to cardiac injury. In order to delay cardiac mitochondrial dysfunction in the context of cardiovascular risk, regular physical activity has been shown to improve mitochondrial parameters and myocardial tolerance to ischemia-reperfusion (IR). Furthermore, pharmacological interventions can prevent the risk of CVDs. Therapeutic agents that can target mitochondria, decreasing ROS production and improve its function have been intensively researched. One example is the mitochondria-targeted antioxidant MitoQ10, which already showed beneficial effects in hypertensive rat models. Carvedilol or antidiabetic drugs also showed protective effects by preventing cardiac mitochondrial oxidative damage. Conclusion: This review highlights the role of mitochondrial dysfunction in CVDs, also show-casing several approaches that act by improving mitochondrial function in the heart, contributing to decrease some of the risk factors associated with CVDs.

No abstract

During embryonic development, cardiomyocytes undergo differentiation and maturation, processes that are tightly regulated by tissue-specific signaling cascades. Although redox signaling pathways involved in cardiomyogenesis are established, the exact sources responsible for reactive oxygen species (ROS) formation remain elusive. The present study investigates whether ROS produced by the mitochondrial flavoenzyme monoamine oxidase A (MAO-A) play a role in cardiomyocyte differentiation from human induced pluripotent stem cells (hiPSCs). Wild type (WT) and MAO-A knock out (KO) hiPSCs were generated by CRISPR/Cas9 genome editing and subjected to cardiomyocyte differentiation. Mitochondrial ROS levels were lower in MAO-A KO compared to the WT cells throughout the differentiation process. MAO-A KO hiPSC-derived cardiomyocytes (hiPSC-CMs) displayed sarcomere disarray, reduced α- to β-myosin heavy chain ratio, GATA4 upregulation and lower macroautophagy levels. Functionally, genetic ablation of MAO-A negatively affected intracellular Ca2+ homeostasis in hiPSC-CMs. Mechanistically, MAO-A generated ROS contributed to the activation of AKT signaling that was considerably attenuated in KO cells. In addition, MAO-A ablation caused a reduction in WNT pathway gene expression consistent with its reported stimulation by ROS. As a result of WNT downregulation, expression of MESP1 and NKX2.5 was significantly decreased in MAO-A KO cells. Finally, MAO-A re-expression during differentiation rescued expression levels of cardiac transcription factors, contractile structure, and intracellular Ca2+ homeostasis. Taken together, these results suggest that MAO-A mediated ROS generation is necessary for the activation of AKT and WNT signaling pathways during cardiac lineage commitment and for the differentiation of fully functional human cardiomyocytes.

Type 2 diabetes (T2D) has increased worldwide at an alarming rate. Metabolic syndrome (MetS) is a major risk factor for T2D development. One of the main reasons for the abrupt rise in MetS incidence, besides a sedentary lifestyle, is the westernized diet consumption, with high content of industrialized foods, rich in added dietary sugars (DS), mainly sucrose and fructose. It has been suggested that a higher intake of DS could impair metabolic function, inducing MetS, and predisposing to T2D. However, it remains poorly explored how excessive DS intake modulates mitochondrial function, a key player in metabolism. This review explores the relationship between increased consumption of DS and mitochondrial dysfunction associated with T2D development, pointing to a contribution of the diet-induced accumulation of advanced glycation end-products (AGEs), with brief insights on the impact of maternal high-sugar diet and AGEs consumption during gestation on offspring increased risk of developing T2D later in life, contributing to perpetuate T2D propagation.

Obesity incidence is rising worldwide, including women of reproductive age, contributing to increased gestations in which Maternal Obesity (MO) occurs. Offspring born to obese mothers present an increased predisposition to develop metabolic (e.g., obesity, diabetes) and cardiovascular disease (CVD). The developmental programming of the metabolic dysfunction in MO offspring can initiate in utero. The different availability of metabolic substrates, namely glucose, can modulate cellular growth, proliferation, and differentiation, resulting in different levels of tissue maturation and function. We defined the remodelling of these early processes as the first hit of metabolic disease programming. Among these, adipocyte early differentiation and gut dysbiosis are initial repercussions occurring in MO offspring, contributing to -tissue-specific dysfunction. The second hit of disease programming can be related to the endocrine–metabolic axis dysregulation. The endocrine–metabolic axis consists of multi-organ communication through the release of factors that are able to regulate the metabolic fate of cells of organs involved in physiological metabolic homeostasis. Upon adipose tissue and gut early dysregulation, these organs’ endocrine function can be programmed to the disrupted release of multiple factors (e.g., adiponectin, leptin, glucagon-like peptide). This can be perceived as a natural mechanism to overcome metabolic frailty in an attempt to prevent or postpone organ-specific disease. However, the action of these hormones on other tissues may potentiate metabolic dysfunction or even trigger disease in organs (liver, pancreas, heart) that were also programmed in utero for early disease. A second phase of the endocrine–metabolic dysregulation happens when the affected organs (e.g., liver and pancreas) self-produce an endocrine response, affecting all of the involved tissues and resulting in a new balance of the endocrine–metabolic axis. Altogether, the second hit exacerbates the organ-specific susceptibility to disease due to the new metabolic environment. The developmental programming of the endocrine–metabolic axis can start a vicious cycle of metabolic adaptations due to the release of factors, leading to an endocrine response that can jeopardize the organism’s function. Diseases programmed by MO can be boosted by endocrine dysregulation, namely Non-Alcoholic Fatty Liver Disease, Non-Alcoholic Fatty Pancreas Disease, and the aggravation of the adipose tissue and gut dysfunction. Chronic metabolic dysregulation can also predispose MO offspring to CVD through the modulation of the endocrine environment and/or the metabolic status. To cease the vicious cycle of MO disease transmission among generations and-provide preventive and specialized prenatal and postnatal care to MO offspring, it is necessary to understand the molecular mechanisms underlying the MO-related disease development. In this review, we summarize most of the developmental programming molecular events of the endocrine–metabolic axis described on the offspring exposed to MO, providing a brief overview of the potential mechanisms that predispose MO offspring to metabolic disease, and discuss the programming of the endocrine–metabolic axis as a plausible mechanism for metabolic disease predisposition in MO offspring.