The majority of the epidemiological evidence over the past few decades has linked high intake of fats, especially saturated fats, to increased risk of diabetes and cardiovascular disease. However, findings of some recent studies (e.g., the PURE study) have contested this association. High saturated fat diets (HFD) have been widely used in rodent research to study the mechanism of insulin resistance and metabolic syndrome. Two separate but somewhat overlapping models—the diacylglycerol (DAG) model and the ceramide model—have emerged to explain the development of insulin resistance. Studies have shown that lipid deposition in tissues such as muscle and liver inhibit insulin signaling via the toxic molecules DAG and ceramide. DAGs activate protein kinase C that inhibit insulin-PI3K-Akt signaling by phosphorylating serine residues on insulin receptor substrate (IRS). Ceramides are sphingolipids with variable acyl group chain length and activate protein phosphatase 2A that dephosphorylates Akt to block insulin signaling. In adipose tissue, obesity leads to infiltration of macrophages that secrete pro-inflammatory cytokines that inhibit insulin signaling by phosphorylating serine residues of IRS proteins. For cardiovascular disease, studies in humans in the 1950s and 1960s linked high saturated fat intake with atherosclerosis and coronary artery disease. More recently, trials involving Mediterranean diet (e.g., PREDIMED study) have indicated that healthy monounsaturated fats are more effective in preventing cardiovascular mortality and coronary artery disease than are low-fat, low-cholesterol diets. Antioxidant and anti-inflammatory effects of Mediterranean diets are potential mediators of these benefits.

The prevalence and incidence of metabolic syndrome is reaching pandemic proportions worldwide, thus warranting an intensive search for novel preventive and treatment strategies. Recent studies have identified a number of soluble factors secreted by adipocytes and myocytes (adipo-/myokines), which link sedentary life style, abdominal obesity, and impairments in carbohydrate and lipid metabolism. In this review, we discuss the metabolic roles of the recently discovered myokine β-aminoisobutyric acid (BAIBA), which is produced by skeletal muscle during physical activity. In addition to physical activity, the circulating levels of BAIBA are controlled by the mitochondrial enzyme alanine: glyoxylate aminotransferase 2 (AGXT2), which is primarily expressed in the liver and kidneys. Recent studies have shown that BAIBA can protect from diet-induced obesity in animal models. It induces transition of white adipose tissue to a “beige” phenotype, which induces fatty acids oxidation and increases insulin sensitivity. While the exact mechanisms of BAIBA-induced metabolic effects are still not well understood, we discuss some of the proposed pathways. The reviewed data provide new insights into the connection between physical activity and energy metabolism and suggest that BAIBA might be a potential novel drug for treatment of the metabolic syndrome and its cardiovascular complications.

Endogenous methylarginines were proposed as cardiovascular risk factors more than two decades ago, however, so far, this knowledge has not led to the development of novel therapeutic approaches. The initial studies were primarily focused on the endogenous inhibitors of nitric oxide synthases asymmetric dimethylarginine (ADMA) and monomethylarginine (MMA) and the main enzyme regulating their clearance dimethylarginine dimethylaminohydrolase 1 (DDAH1). To date, all the screens for DDAH1 activators performed with the purified recombinant DDAH1 enzyme have not yielded any promising hits, which is probably the main reason why interest towards this research field has started to fade. The relative contribution of the second DDAH isoenzyme DDAH2 towards ADMA and MMA clearance is still a matter of controversy. ADMA, MMA and symmetric dimethylarginine (SDMA) are also metabolized by alanine: glyoxylate aminotransferase 2 (AGXT2), however, in addition to methylarginines, this enzyme also has several cardiovascular protective substrates, so the net effect of possible therapeutic targeting of AGXT2 is currently unclear. Recent studies on regulation and functions of the enzymes metabolizing methylarginines have given a second life to this research direction. Our review discusses the latest discoveries and controversies in the field and proposes novel directions for targeting methylarginines in clinical settings.

L-arginine and its derivatives, asymmetric and symmetric dimethylarginine (ADMA and SDMA) and L-homoarginine, have emerged as cardiovascular biomarkers linked to cardiovascular outcomes and various metabolic and functional pathways such as NO-mediated endothelial function. Cellular uptake and efflux of L-arginine and its derivatives are facilitated by transport proteins. In this respect the cationic amino acid transporters CAT1 and CAT2 (SLC7A1 and SLC7A2) and the system y⁺L amino acid transporters (SLC7A6 and SLC7A7) have been most extensively investigated, so far, but the number of transporters shown to mediate the transport of L-arginine and its derivatives is constantly increasing. In the present review we assess the growing body of evidence regarding the function, expression, and clinical relevance of these transporters and their possible relation to cardiovascular diseases.

Low plasma concentrations of L-homoarginine are associated with an increased risk of cardiovascular events, while homoarginine supplementation is protective in animal models of metabolic syndrome and stroke. Catabolism of homoarginine is still poorly understood. Based on the recent findings from a Genome Wide Association Study we hypothesized that homoarginine can be metabolized by alanine:glyoxylate aminotransferase 2 (AGXT2). We purified human AGXT2 from tissues of AGXT2 transgenic mice and demonstrated its ability to metabolize homoarginine to 6-guanidino-2-oxocaproic acid (GOCA). After incubation of HepG2 cells overexpressing AGXT2 with isotope-labeled homoarginine-d4 we were able to detect labeled GOCA in the medium. We injected wild type mice with labeled homoarginine and detected labeled GOCA in the plasma. We found that AGXT2 knockout (KO) mice have higher homoarginine and lower GOCA plasma levels as compared to wild type mice, while the reverse was true for AGXT2 transgenic (Tg) mice. In summary, we experimentally proved the presence of a new pathway of homoarginine catabolism – its transamination by AGXT2 with formation of GOCA and demonstrated that endogenous AGXT2 is required for maintenance of homoarginine levels in mice. Our findings may lead to development of novel therapeutic approaches for cardiovascular pathologies associated with homoarginine deficiency.

Background: Homoarginine ( hA rg) has been shown to be cardioprotective in a model of ischemic heart failure; however, the mechanism remains unknown. hA rg can inhibit tissue‐nonspecific alkaline phosphatase ( TNAP ), an enzyme that promotes vascular calcification. We hypothesized that hA rg will exert beneficial effects by reducing calcification in a mouse model of coronary artery disease associated with TNAP overexpression and hypercholesterolemia. Methods and Results: TNAP was overexpressed in the endothelium in mice homozygous for a low‐density lipoprotein receptor mutation (wicked high cholesterol [ WHC ] allele). WHC and WHC –endothelial TNAP mice received placebo or hA rg supplementation (14 mg/L in drinking water) starting at 6 weeks of age simultaneously with an atherogenic diet. Outcomes were compared between the groups after 4 to 5 weeks on treatment. Experiments were performed in males, which presented a study limitation. As expected, WHC –endothelial TNAP mice on the placebo had increased mortality (median survival 27 days, P <0.0001), increased coronary calcium and lipids ( P <0.01), increased left ventricular end‐diastolic diameter ( P <0.0001), reduced ejection fraction ( P <0.05), and increased myocardial fibrosis ( P <0.0001) compared with WHC mice. Contrary to our hypothesis, hA rg neither inhibited TNAP activity in vivo nor reduced coronary artery calcification and atherosclerosis in WHC –endothelial TNAP mice; however, compared with the placebo, hA rg prevented left ventricular dilatation ( P <0.01), preserved ejection fraction ( P <0.05), and reduced myocardial fibrosis ( P <0.001). Conclusions: The beneficial effect of hA rg supplementation in the setting of calcified coronary artery disease is likely due to its direct protective actions on the myocardial response to the ischemic injury and not to the inhibition of TNAP activity and calcification.