Modulation of contractility by myocyte-derived arginase in normal and hypertrophied feline myocardium

Abstract

. Modulation of contractility by myocytederived arginase in normal and hypertrophied feline myocardium. Am J Physiol Heart Circ Physiol 290: H1756 -H1762, 2006. First published December 3, 2005 doi:10.1152/ajpheart.01104.2005.-L-Arginine, the sole substrate for the nitric oxide (NO) synthase (NOS) enzyme in producing NO, is also a substrate for arginase. We examined normal feline hearts and hearts with compensated left ventricular (LV) hypertrophy (LVH) produced by ascending aorta banding. Using Western blot analysis, we examined the abundance of arginase isozymes in crude homogenates and isolated cardiac myocytes obtained from the LVs of normal and LVH hearts. We examined the functional significance of myocyte arginase via measurement of shortening and intracellular calcium in isolated myocytes in the presence and absence of boronoethyl chloride (BEC), a specific pharmacological inhibitor of arginase. Both arginase I and II were detected in crude myocardial homogenates, but only arginase I was present in isolated cardiac myocytes. Arginase I was downregulated in LVH compared with normal. Inhibition of arginase with BEC reduced fractional shortening, maximal rate of shortening (ϩdL/dt) and relengthening (ϪdL/dt), and the peak of the free cytosolic calcium transient in normal myocytes but did not affect these parameters in LVH myocytes. These negative inotropic actions of arginase inhibition were associated with increases in cGMP generation. These studies indicate that only arginase I is present in cardiac myocytes where it tends to limit NO and cGMP production with the effect of supporting basal contractility. In experimental LVH induced by pressure overload, our studies demonstrate reduced arginase I expression and reduced functional significance, allowing greater arginine substrate availability for NO/cGMP signaling.arginase; hypertrophy; nitric oxide; guanosine 3Ј,5Ј-cyclic monophosphate; calcium AS IN THE VASCULATURE, nitric oxide (NO) synthase (NOS) regulates the generation of NO in cardiac myocytes by deaminating the amino acid substrate L-arginine to produce NO and citrulline. NO modulates cardiac contractility via activation of soluble guanylyl cyclase, inducing increases in cGMP. In turn, cGMP modulates contractility via the activation of certain phosphodiesterases, activation of protein kinase G, and by direct stimulation of calcium cycling proteins. On the other hand, there are reports that NO can alter contractility independent of cGMP by direct nitrosylation or acetylation of various channels and calcium cycling proteins.In the normal myocardium, the acute effects of increases in NO are bimodal, with a positive inotropic effect at low amounts of NO exposure but a negative one at higher amounts (28). NO donors have been shown to exhibit weak to moderate negative inotropic effects in nondiseased preparations (8,25,34). On the other hand, in pathological states, there is increasing evidence that upregulation of NOS and/or increased production of NO improves left ventricular (LV) performance and myocyt...

Misregulation of the arginase pathway in tissues of spontaneously hypertensive rats

“…[2][3][4][5][6] In our study, normotensive WKY rats exhibit substantial arginase activity in all organs studied, which is associated with the expression of both arginase isoforms in the brain, lungs and heart, and with the expression of arginase I in the liver and arginase II in the kidney. These data are in accordance with previous studies reporting the expression of arginase I and/or II in neurons, 16,17 cardiomyocytes, 18,19 pulmonary epithelial, endothelial, smooth muscle cells, fibroblasts and alveolar macrophages, 20 in renal proximal straight tubules and inner medullary collecting ducts, 21,22 as well as in hepatocytes. 21 A new finding of our study is the age-dependent increase in arginase activity in the heart of WKY rats.…”

“…These data suggest that cardiac arginase is a target of age-associated metabolic dysfunctions and complete recent studies showing increased vascular 23 and penile 24 arginase in old animals. Given that aging is associated with impaired myocardial contractility 25 and that arginase activity was reported to modulate cardiomyocyte contractility through an NO-dependent mechanism, 18,19 this result opens new avenues on the role of arginase in cardiac dysfunction associated with aging.…”

Strategic localization of heart mitochondrial NOS: a review of the evidence

“…However, rather lower intracellular levels of L-arginine were reported in cardiomyocytes (42). Moreover, the expression of arginase II in mitochondria of mouse cardiac myocytes (122) and arginase I in feline cardiac myocytes (69) has been demonstrated. The activity of mtNOS may be impaired under the conditions whereby L-arginine concentration within the heart mitochondria is diminished.…”

Inducible NO Synthase–Dependent S -Nitrosylation and Activation of Arginase1 Contribute to Age-Related Endothelial Dysfunction

“…[5][6][7][8] Increased arginase activity, therefore, leads to diminished production of NO. 6,[9][10][11][12] In vascular tissue, this further affects 2 important functions of NO: (1) cGMPdependent signaling and (2) modulation of protein function through S-nitrosylation. Several studies have demonstrated reciprocal regulation of arginase and NOS, where inhibition of arginase leads to increased NO activity.…”