Augmented endothelial l‐arginine transport ameliorates pressure‐overload‐induced cardiac hypertrophy

Abstract

New Findings r What is the central question of this study?What is the potential role of endothelial NO production via overexpression of the l-arginine transporter, CAT1, as a mitigator of cardiac hypertrophy? r What is the main finding and its importance?Augmentation of endothelium-specific l-arginine transport via CAT1 can attenuate pressure-overload-dependent cardiac hypertrophy and fibrosis. Our findings support the conclusion that interventions that improve endothelial l-arginine transport may provide therapeutic utility in the setting of myocardial hypertrophy. Such modifications may be introduced by exercise training or locally delivered gene therapy, but further experimental and clinical studies are required.Endothelial dysfunction has been postulated to play a central role in the development of cardiac hypertrophy, probably as a result of reduced NO bioavailability. We tested the hypothesis that increased endothelial NO production, mediated by increased l-arginine transport, could attenuate pressure-overload-induced cardiac hypertrophy. Echocardiography and blood pressure measurements were performed 15 weeks after transverse aortic constriction (TAC) in wild-type (WT) mice (n = 12) and in mice with endothelium-specific overexpression of the l-arginine transporter, CAT1 (CAT+; n = 12). Transverse aortic constriction induced greater increases in heart weight to body weight ratio in WT (by 47%) than CAT+ mice (by 25%) compared with the respective controls (P ࣘ 0.05). Likewise, the increase in left ventricular wall thickness induced by TAC was significantly attenuated in CAT+ mice (P = 0.05). Cardiac collagen type I mRNA expression was greater in WT mice with TAC (by 22%; P = 0.03), but not in CAT+ mice with TAC, compared with the respective controls. Transverse aortic constriction also induced lesser increases in β-myosin heavy chain mRNA expression in CAT+ mice compared with WT (P ࣘ 0.05). Left ventricular systolic pressure after TAC was 36 and 39% greater in WT and CAT+ mice, respectively, compared with the respective controls (P ࣘ 0.001). Transverse aortic constriction had little effect on left ventricular end-diastolic pressure in both genotypes. Taken together, these data indicate that augmenting endothelial function by overexpression of l-arginine transport can attenuate pressure-overload-induced cardiac hypertrophy.

The Vascular Endothelium in Chronic Kidney Disease

“…In support of this hypothesis, endothelial-specific overexpression of CAT-1 has recently been reported to prevent pressure overload-induced cardiac hypertrophy in mice (33) and we have recently demonstrated preserved cardiac function in a rodent model of CKD subjected to 4-weeks of voluntary wheel running (19). While the combined effect of exercise and L-arginine supplementation on cardiac function in CKD has not yet been tested, these findings collectively suggest that aerobic exercise and sufficient endothelial L-arginine transport are important for the maintenance of cardiac function.…”

N- acetylcysteine attenuates the development of cardiac fibrosis and remodeling in a mouse model of heart failure

“…; Rajapakse et al. ). In brief, m‐mode two‐dimensional echocardiography was performed using a Philips iE33 echocardiography system (Royal Philips Electronics, Amsterdam, Netherlands) with a 15‐MHz linear array transducer.…”

“…Isoflurane (3-4.5% induction and 1.5-2% maintenance delivered through a mask) was used to anesthetize mice and echocardiography was performed as we have previously described (Chu et al 2011;Rajapakse et al 2015). In brief, m-mode two-dimensional echocardiography was performed using a Philips iE33 echocardiography system (Royal Philips Electronics, Amsterdam, Netherlands) with a 15-MHz linear array transducer.…”

Insulin requires A1 adenosine receptors expression to reverse gestational diabetes-increased L-arginine transport in human umbilical vein endothelium

“…In HUVECs from GDM, the overall Larginine transport was semisaturable with a non-saturable Larginine transport component (K D ) detected from L-arginine concentrations >250 μM, suggesting that L-arginine transport was likely mediated by at least two membrane transport mechanisms in this cell type. The possibility that hCAT-1 mediates L-arginine transport is likely since the apparent K m value for saturable transport is within the range of this transport system in HUVECs [6,18] and other cell types [14,15,19,20]. In addition, L-arginine transport was trans-stimulated by~7-fold only when a concentration of L-arginine (100 μM in this study) was close to the K m for hCAT-1.…”

“…This phenomenon is maintained by a higher expression of the SLC7A1 gene for hCAT-1 leading to higher hCAT-1 mRNA expression and protein abundance. stimulation of hCAT-1-mediated L-arginine transport by Llysine is known to be higher (~5-10 fold) than hCAT-2B-mediated transport (~2-3 fold) [14,15,[19][20][21], involvement of hCAT-2B transport activity in HUVECs from GDM pregnancies is unlikely.…”