Homoarginine Supplementation Prevents Left Ventricular Dilatation and Preserves Systolic Function in a Model of Coronary Artery Disease

Abstract

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.

TNAP inhibition attenuates cardiac fibrosis induced by myocardial infarction through deactivating TGF-β1/Smads and activating P53 signaling pathways

“…Reduction TNAP by short hairpin RNA was reported significantly reduced prostate cancer cells migration with lower vimentin expression 29 . Rodionov et al 6 also reported in a mouse model of coronary artery disease that endothelial TNAP overexpression transgenic mice associated with increased myocardial fibrosis. Both were consistent with our results.…”

“…Animal experiment observed an upregulation of TNAP in fibrotic heart 4 . Latest studies of TNAP on cardiac fibrosis demonstrated controversial results 5,6 . The effects of TNAP on cardiac fibrosis and its underlying mechanism are still not clear.…”

Homoarginine- and Creatine-Dependent Gene Regulation in Murine Brains with l-Arginine:Glycine Amidinotransferase Deficiency

“…In contrast to the present study, the previous analysis in skeletal muscle did not include a validation in a second independent cohort. Creatine supplementation completely normalized the metabolic phenotype of AGAT −/− mice (i.e., weight, glucose and lipid metabolism), whereas only hArg supplementation improved post-myocardial infarction heart failure, diabetic kidney damage, systolic function in a model of coronary artery disease and reduced neointimal hyperplasia in balloon-injured rat carotids [15,17,18,29]. Interestingly, hArg normalized a number of cardiac parameters, which are highly calcium-dependent despite unaltered intracellular calcium levels [15,31].…”

“…The supplementation with hArg, but not creatine, significantly reduced infarct sizes and improved outcome [9]. In addition to experimental stroke models, hArg supplementation proved protective in murine models of post-myocardial infarction heart failure, diabetic kidney disease, coronary artery disease and balloon-injured carotids [15][16][17][18]. However, data on the underlying molecular mechanisms and signal transduction pathways in the AGAT metabolism is still very limited.…”

Arginine Derivatives in Cerebrovascular Diseases: Mechanisms and Clinical Implications

“…First, AGAT-deficient mice are devoid of hArg and revealed increased infarct sizes and an impaired cardiac contractibility, which were normalized upon hArg supplementation [91,102]. Furthermore, hArg supplementation attenuated detrimental effects of diabetic kidney damage, preserved systolic function in a model of coronary artery disease, reduced neointimal hyperplasia in balloon-injured rat carotids and attenuated post-myocardial infarction heart failure [91,[103][104][105][106].…”