Why epigenetics is (not) a biosocial science and why that matters

Epigenetic modifications offer compelling evidence of the environmental etiology of complex diseases. Social and biographical conditions, as well as material exposures, all modulate our biology with consequences for risk predispositions and health conditions. Elucidating these complex biosocial loops is one of the main challenges animating epigenetics. Yet, research on the development of epigenetic biomarkers often pulls in a direction that departs from a view of biological determinants of health embedded in their social and material environment. Taking the example of the epigenetics of cardiovascular diseases, this paper illustrates how common understandings of epigenetic biomarkers strongly lean toward considering them as mere targets for molecular intervention, rather than as correlates of a complex biological and social patterning of disease. This reductionism about biosocial dynamics of disease, we argue, hampers the pursuit of the goals epigenetics has given itself (in cardiology and beyond). If epigenetic mechanisms point to the deep socio-environmental embeddedness of our health, we conclude, future designs and methods of this research may require an improved methodological consideration of a biosocial perspective

Why epigenetics is (not) a biosocial science and why that matters

Epigenetic modifications offer compelling evidence of the environmental etiology of complex diseases. Social and biographical conditions, as well as material exposures, all modulate our biology with consequences for risk predispositions and health conditions. Elucidating these complex biosocial loops is one of the main challenges animating epigenetics. Yet, research on the development of epigenetic biomarkers often pulls in a direction that departs from a view of biological determinants of health embedded in their social and material environment. Taking the example of the epigenetics of cardiovascular diseases, this paper illustrates how common understandings of epigenetic biomarkers strongly lean toward considering them as mere targets for molecular intervention, rather than as correlates of a complex biological and social patterning of disease. This reductionism about biosocial dynamics of disease, we argue, hampers the pursuit of the goals epigenetics has given itself (in cardiology and beyond). If epigenetic mechanisms point to the deep socio-environmental embeddedness of our health, we conclude, future designs and methods of this research may require an improved methodological consideration of a biosocial perspective

A ‘Once-and-Done’ Approach to the Lifelong Reduction of Elevated Cholesterol

Key points CRISPR (clustered regularly interspaced short palindromic repeats)-related technologies are emerging therapeutic strategies to induce DNA modifications in humans. In this regard, gene editing of proprotein convertase subtilisin/kexin type 9 (PCSK9) might represent a promising approach for the prevention of coronary heart disease (CHD). The present study1 investigates the impact of a single-nucleotide PCSK9 loss-of-function mutation by CRISPR adenine base editors (ABE) on low-density lipoprotein cholesterol (LDL-C) levels in non-human primates. To introduce a precise single-nucleotide PCSK9 loss-of-function mutation, a CRISPR ABE was delivered in macaques using lipid nanoparticles (LNPs). Adenine base editors of PCSK9 was confirmed in primary human hepatocytes, primary monkey hepatocytes, and mice. In vivo CRISPR ABE delivery led to a near-complete knockdown of PCSK9 in the liver after a single infusion of LNPs, with concomitant reductions in blood levels of PCSK9 and LDL-C of ∼90% and 60%, respectively. These changes were sustained for at least 8 months after a single-dose treatment. No relevant side effects were observed in the animals treated with a CRISPR editor-based strategy. Off-target gene editing was found at only one site in macaque liver, whereas no off-target editing was found in human hepatocytes

Exploring RNA biomarkers in patients with acute myocarditis

No abstract availabl

Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I

Hyperglycemia and insulin resistance are key players in the development of atherosclerosis and its complications. A large body of evidence suggest that metabolic abnormalities cause overproduction of reactive oxygen species (ROS). In turn, ROS, via endothelial dysfunction and inflammation, play a major role in precipitating diabetic vascular disease. A better understanding of ROS-generating pathways may provide the basis to develop novel therapeutic strategies against vascular complications in this setting. Part I of this review will focus on the most current advances in the pathophysiological mechanisms of vascular disease: (i) emerging role of endothelium in obesity-induced insulin resistance; (ii) hyperglycemia-dependent microRNAs deregulation and impairment of vascular repair capacities; (iii) alterations of coagulation, platelet reactivity, and microparticle release; (iv) epigenetic-driven transcription of ROS-generating and proinflammatory genes. Taken together these novel insights point to the development of mechanism-based therapeutic strategies as a promising option to prevent cardiovascular complications in diabete

Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I

Hyperglycemia and insulin resistance are key players in the development of atherosclerosis and its complications. A large body of evidence suggest that metabolic abnormalities cause overproduction of reactive oxygen species (ROS). In turn, ROS, via endothelial dysfunction and inflammation, play a major role in precipitating diabetic vascular disease. A better understanding of ROS-generating pathways may provide the basis to develop novel therapeutic strategies against vascular complications in this setting. Part I of this review will focus on the most current advances in the pathophysiological mechanisms of vascular disease: (i) emerging role of endothelium in obesity-induced insulin resistance; (ii) hyperglycemia-dependent microRNAs deregulation and impairment of vascular repair capacities; (iii) alterations of coagulation, platelet reactivity, and microparticle release; (iv) epigenetic-driven transcription of ROS-generating and proinflammatory genes. Taken together these novel insights point to the development of mechanism-based therapeutic strategies as a promising option to prevent cardiovascular complications in diabetes

Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II

In part II of this review, we describe the epidemiology and clinical consequences of vascular disease in patients with diabetes, and discuss the efficacy of risk factor modification and antiplatelet treatment. Specifically, evidence-based cardiovascular therapies are discussed through novel clinical insights on management of hyperglycaemia, hypertension, dyslipidaemia as well as platelet dysfunction. Recent trends in the incidence and outcomes of vascular disease in diabetes suggest that timely and effective implementation of therapies is making a favourable impac

Modulating Sirtuin Biology and Nicotinamide Adenine Diphosphate Metabolism in Cardiovascular Disease—From Bench to Bedside

Sirtuins (SIRT1–7) comprise a family of highly conserved deacetylases with distribution in different subcellular compartments. Sirtuins deacetylate target proteins depending on one common substrate, nicotinamide adenine diphosphate (NAD+), thus linking their activities to the status of cellular energy metabolism. Sirtuins had been linked to extending life span and confer beneficial effects in a wide array of immune-metabolic and cardiovascular diseases. SIRT1, SIRT3, and SIRT6 have been shown to provide protective effects in various cardiovascular disease models, by decreasing inflammation, improving metabolic profiles or scavenging oxidative stress. Sirtuins may be activated collectively by increasing their co-substrate NAD+. By supplementing NAD+ precursors, NAD+ boosters confer pan-sirtuin activation with protective cardiometabolic effects in the experimental setting: they improve endothelial dysfunction, protect from experimental heart failure, hypertension and decrease progression of liver steatosis. Different precursor molecules were applied ranging from nicotinamide (NAM), nicotinamide mononucleotide (NMN) to nicotinamide riboside (NR). Notably, not all experimental results showed protective effects. Moreover, the results are not as striking in clinical studies as in the controlled experimental setting. Species differences, (lack of) genetic heterogeneity, different metabolic pathways, dosing, administration routes and disease contexts may account for these challenges in clinical translation. At the clinical scale, caloric restriction can reduce the risks of cardiovascular disease and raise NAD+ concentration and sirtuin expression. In addition, antidiabetic drugs such as metformin or SGLT2 inhibitors may confer cardiovascular protection, indirectly via sirtuin activation. Overall, additional mechanistic insight and clinical studies are needed to better understand the beneficial effects of sirtuin activation and NAD+ boosters from bench to bedside