SummaryThe citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). To compensate for the loss of Fh1 activity, KO hearts maintain ATP levels in part by channeling amino acids into the CAC. In addition, by stabilizing the transcriptional regulator Nrf2, Fh1 KO hearts upregulate protective antioxidant response element genes. Supporting the importance of the latter mechanism, clinically relevant doses of dimethylfumarate upregulated Nrf2 and its target genes, hence protecting control hearts, but failed to similarly protect Nrf2-KO hearts in an in vivo model of myocardial infarction. We propose that clinically established fumarate derivatives activate the Nrf2 pathway and are readily testable cytoprotective agents.

Abstract-Offspring born to mothers with hypertensive pregnancy have higher childhood blood pressure. We hypothesized this relates to prenatally programmed differences in the underlying vascular pathophysiology of the offspring and that these would be most apparent in those born preterm because of severe hypertension. We carried out a 20-year follow-up study of 71 subjects born preterm, 19 to a hypertensive pregnancy and 52 to a normotensive pregnancy. Findings were compared with 38 subjects born at term to uncomplicated pregnancies. Peripheral and central blood pressures were measured, and then central arterial stiffness was assessed by carotid-femoral pulse wave velocity using applanation tonometry. Ultrasound was used to assess flow-mediated endothelial-dependent and independent brachial artery responses and common carotid artery intima-media thickness. Key Words: blood pressure Ⅲ preeclampsia Ⅲ endothelial function Ⅲ fetal programming Ⅲ prematurity D e novo onset hypertension affects 5% to 7% of all pregnancies 1 and is manifest as a spectrum of hypertensive complications ranging from gestational hypertension to severe preeclampsia. 2 Hypertensive pregnancy has 3,4 emerged as an independent risk factor for premature maternal cardiovascular disease, 1,5,6 and recently offspring of hypertensive pregnancies have also been found to be at greater risk of higher blood pressure in childhood 7-11 and stroke in later life. 12 Furthermore, the risk to the offspring is graded and greatest in those whose mothers had more severe hypertensive signs, such as early onset hypertension or preeclampsia. 12 Severe hypertensive pregnancy is commonly associated with premature delivery and intrauterine growth restriction. 13 Prematurity and growth restriction, in turn, have been independently linked with hypertension and cardiovascular complications in the offspring, 14 -16 and it is postulated that this is mediated through intrauterine conditions adversely affecting the development of the offspring vascular system. 17 Interestingly, despite both prematurity and intrauterine growth restriction leading to the same clinical sequelae of hypertension, the persistent underlying vascular phenotype appears to vary with, for example, only the term intrauterine growthrestricted offspring exhibiting endothelial dysfunction. 15,18 -20 Better understanding of the long-term changes in vascular pathophysiology related to different pregnancy complications may allow novel primary cardiovascular prevention strategies targeted at key aspects of vascular function. 21

Inhibition of the MA-shuttle during ischaemia and early reperfusion is proposed as a mechanism to reduce IR injury.