A novel signaling pathway of ADP-ribosyl cyclase activation by angiotensin II in adult rat cardiomyocytes

Abstract

ADP-ribosyl cyclase (ADPR-cyclase) produces a Ca(2+)-mobilizing second messenger, cADP-ribose (cADPR), from NAD(+). In this study, we investigated the molecular basis of ADPR-cyclase activation in the ANG II signaling pathway and cellular responses in adult rat cardiomyocytes. The results showed that ANG II generated biphasic intracellular Ca(2+) concentration increases that include a rapid transient Ca(2+) elevation via inositol trisphosphate (IP(3)) receptor and sustained Ca(2+) rise via the activation of L-type Ca(2+) channel and opening of ryanodine receptor. ANG II-induced sustained Ca(2+) rise was blocked by a cADPR antagonistic analog, 8-bromo-cADPR, indicating that sustained Ca(2+) rise is mediated by cADPR. Supporting the notion, ADPR-cyclase activity and cADPR production by ANG II were increased in a time-dependent manner. Application of pharmacological inhibitors and immunological analyses revealed that cADPR formation was activated by sequential activation of Src, phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (Akt), phospholipase C (PLC)-gamma1, and IP(3)-mediated Ca(2+) signal. Inhibitors of these signaling molecules not only completely abolished the ANG II-induced Ca(2+) signals but also inhibited cADPR formation. Application of the cADPR antagonist and inhibitors of upstream signaling molecules of ADPR-cyclase inhibited ANG II-stimulated hypertrophic responses, which include nuclear translocation of Ca(2+)/calcineurin-dependent nuclear factor of activated T cells 3, protein expression of transforming growth factor-beta1, and incorporation of [(3)H]leucine in cardiomyocytes. Taken together, these findings suggest that activation of ADPR-cyclase by ANG II entails a novel signaling pathway involving sequential activation of Src, PI 3-kinase/Akt, and PLC-gamma1/IP(3) and that the activation of ADPR-cyclase can lead to cardiac hypertrophy.

BLX-1002, a novel thiazolidinedione with no PPAR affinity, stimulates AMP-activated protein kinase activity, raises cytosolic Ca2+, and enhances glucose-stimulated insulin secretion in a PI3K-dependent manner

“…Knockout of PI3K-␥ in mice, or transfection of small interfering RNA against PI3K-␥ in ␤-cells, significantly inhibits glucose-stimulated insulin secretion (37). The partial inhibition in the [Ca 2ϩ ] i response and complete inhibition in BLX-1002-induced insulin secretion by the specific PI3K inhibitor suggest that this kinase may be involved both in the regulation of [Ca 2ϩ ] i (19,40) and insulin exocytosis (16). Considering that the PI3K inhibitors wortmannin and LY-294002 have no selectivity for individual PI3K isoforms (28) and that different isoforms of PI3K may play different roles in insulin secretion (16,37), the PI3K isoform involved in BLX-1002-induced insulin secretion requires further investigation.…”

CD38 Mediates Angiotensin II–Induced Intracellular Ca2+ Release in Rat Pulmonary Arterial Smooth Muscle Cells

“…CD38 expression has been reported in some systemic arteries, including aorta and the coronary and renal arteries (8)(9)(10). Endogenous vasoconstrictors, such as norepinephrine, endothelin-1 (ET-1), and angiotensin II (Ang II), have been shown to activate the cyclase and catalase activities of CD38, contributing to the elevation of [Ca 21 ] i and vasoconstriction (11)(12)(13)(14)(15)(16). In general, these vasoconstrictory agonists of G-protein-coupled receptors activate phospholipase C (PLC) to synthesize inositol trisphosphate (IP 3 ) and diacyglycerol from phosphatidylinositol bisphosphate.…”

Role of kidney ADP-ribosyl cyclase in diabetic nephropathy

“…Ϫ/Ϫ and CD38 ϩ/ϩ cardiomyocytes but that 8-Br-cADPR completely inhibited the ANG II-induced sustained Ca 2ϩ increase, indicating that cADPR is generated by a novel ADPR-cyclase (8). We also demonstrated that the kidney ADPR-cyclase-selective blocking compound 4,4Ј-dihydroxyazobenzene (DHAB) protects ANG II-mediated mesangial cell growth (16).…”