Interplay between Oxidative Stress and Nutrient Sensing Signaling in the Developmental Origins of Cardiovascular Disease

Abstract

Cardiovascular disease (CVD) presents a global health burden, despite recent advances in management. CVD can originate from early life by so-called "developmental origins of health and disease" (DOHaD). Epidemiological and experimental evidence supports that early-life insults can induce programming of later CVD. Underlying the DOHaD concept, early intervention may offset programming process to prevent the development of CVD, namely reprogramming. Oxidative stress and nutrient sensing signals have been considered to be major mechanisms of cardiovascular programming, while the interplay between these two mechanisms have not been examined in detail. This review summarizes current evidence that supports the link between oxidative stress and nutrient sensing signaling to cardiovascular programming, with an emphasis on the l-arginine-asymmetric dimethylarginine (ADMA)-nitric oxide (NO) pathway. This review provides an overview of evidence from human studies supporting fetal programming of CVD, insight from animal models of cardiovascular programming and oxidative stress, impact of the l-arginine-ADMA-NO pathway in cardiovascular programming, the crosstalk between l-arginine metabolism and nutrient sensing signals, and application of reprogramming interventions to prevent the programming of CVD. A greater understanding of the mechanisms underlying cardiovascular programming is essential to developing early reprogramming interventions to combat the globally growing epidemic of CVD.

Keywords: arginine; asymmetric dimethylarginine; cardiovascular disease; developmental origins of health and disease (DOHaD); hypertension; nitric oxide; nutrient sensing; oxidative stress; phytonutrient; symmetric dimethylarginine.

Figure 1

A schema showing that early-life environmental insults affect the l-arginine–ADMA–NO pathway, increase oxidative stress, and dysregulate nutrient sensing signals, leading to cardiovascular programming and cardiovascular disease (CVD) in later life. Early targeting of the above mechanisms might serve as a reprogramming approach to prevent CVD and its related comorbidities in adulthood. ↑ = increased. ↓ = decreased.

Figure 2

The synthesis and metabolism of l-arginine, asymmetric dimethylarginine (ADMA), and l-citrulline. l-arginine has multiple metabolic fates, including metabolism by NOS, arginase, and other enzymes. ADMA can compete with l-arginine to reduce the synthesis of NO. Both ADMA and symmetric dimethylarginine (SDMA) come from methylated l-arginine by protein arginine methyltransferase (PRMT). ADMA can be transported to other organs or excreted into the urine. Unlike SDMA, only ADMA can be metabolized by dimethylarginine dimethylaminohydrolase (DDAH)-1 and -2. Alanine-glyoxylate aminotransferase 2 (AGXT2) can metabolize ADMA as well as SDMA. l-citrulline can be generated by NOS, DDAHs, and ornithine carbamoyltransferase (OCT). l-citrulline can be used to make l-arginine via the argininosuccinate (AS) pathway. ADMA can uncouple NOS to produce reactive oxygen species (ROS). ROS can induce PRMT and inhibit DDAH activity, leading to an increase in ADMA.

Figure 3

A schema showing the interplay between nutrient sensing signals and oxidative stress on the regulation of PPARγ coactivator-1α (PGC-1α), peroxisome proliferator-activated receptor (PPAR) target genes, mitochondria biogenesis, and autophagy. ↑ = increased. ↓ = decreased.