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Differential Regulation of Inotropy and Lusitropy in Overexpressed Gsα Myocytes Through Camp and Ca2+ Channel Pathways

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Differential Regulation of Inotropy and Lusitropy in Overexpressed Gsα Myocytes Through Camp and Ca2+ Channel Pathways Differential regulation of inotropy and lusitropy in overexpressed Gsα myocytes through cAMP and Ca2+ channel pathways Song-Jung Kim, … , Charles J. Homcy, Stephen F. Vatner J Clin Invest. 1999;103(7):1089-1097. https://doi.org/10.1172/JCI4848. Article We investigated the mechanisms responsible for altered contractile and relaxation function in overexpressed Gsα myocytes. Although baseline contractile function (percent contraction) in Gsα mice was similar to that of wild-type (WT) 2+ 2+ mice, left ventricular myocyte contraction, fura-2 Ca transients, and Ca channel currents (ICa) were greater in Gsα mice in response to 10–8 M isoproterenol (ISO) compared with WT mice. The late phase of relaxation of the isolated myocytes and fura-2 Ca2+ transients was accelerated at baseline in Gsα but did not increase further with ISO.I n vivo measurements using echocardiography also demonstrated enhanced relaxation at baseline in Gsα mice. Forskolin and CaCl2 increased contraction similarly in WT and Gsα mice. Rp-cAMP, an inhibitor of protein kinase, blocked the increases in contractile response and Ca2+ currents to ISO in WT and to forskolin in both WT and Gsα. It also blocked the accelerated relaxation in Gsα at baseline but not the contractile response to ISO in Gsα myocytes. Baseline measurements of cAMP and phospholambation phosphorylation were enhanced in Gsα compared with WT. These data indicate that overexpression of Gsα accelerates relaxation at end diastolic but does not affect baseline systolic function in isolated myocytes. However, the enhanced responses to sympathetic stimulation partly reflect increased Ca2+ channel activity; i.e the cellular mechanisms mediating these effects appear to involve a cAMP-independent as well […] Find the latest version: https://jci.me/4848/pdf Differential regulation of inotropy and lusitropy in overexpressed Gsα myocytes through cAMP and Ca2+ channel pathways Song-Jung Kim,1 Atsuko Yatani,1 Dorothy E. Vatner,1 Satoshi Yamamoto,1 Yoshihiro Ishikawa,1 Thomas E. Wagner,2 Richard P. Shannon,1 Young-Kwon Kim,1 Gen Takagi,1 Kuniya Asai,1 Charles J. Homcy,3 and Stephen F. Vatner1 1Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212, USA 2Department of Molecular Medicine, Clemson University, and the Greenville Hospital System/Clemson University Biomedical Cooperative, Greenville, South Carolina 29605, USA 3COR Therapeutics Inc., South San Francisco, California 94080, USA Address correspondence to: Stephen F. Vatner, Cardiovascular Research Institute, Allegheny University of the Health Sciences, 15th floor, South Tower, 320 East North Avenue, Pittsburgh, Pennsylvania 15212, USA. Phone: (412) 359-8255; Fax: (412) 359-8257; E-mail: [email protected] Received for publication August 7, 1998, and accepted in revised form February 23, 1999. We investigated the mechanisms responsible for altered contractile and relaxation function in overex- pressed Gsα myocytes. Although baseline contractile function (percent contraction) in Gsα mice was similar to that of wild-type (WT) mice, left ventricular myocyte contraction, fura-2 Ca2+transients, and 2+ –8 Ca channel currents (Ica) were greater in Gsα mice in response to 10 M isoproterenol (ISO) compared with WT mice. The late phase of relaxation of the isolated myocytes and fura-2 Ca2+ transients was accel- erated at baseline in Gsα but did not increase further with ISO. In vivo measurements using echocar- diography also demonstrated enhanced relaxation at baseline in Gsα mice. Forskolin and CaCl2 increased contraction similarly in WT and Gsα mice. Rp-cAMP, an inhibitor of protein kinase, blocked the increases in contractile response and Ca2+ currents to ISO in WT and to forskolin in both WT and Gsα. It also blocked the accelerated relaxation in Gsα at baseline but not the contractile response to ISO in Gsα myocytes. Baseline measurements of cAMP and phospholambation phosphorylation were enhanced in Gsα compared with WT. These data indicate that overexpression of Gsα accelerates relax- ation at end diastolic but does not affect baseline systolic function in isolated myocytes. However, the enhanced responses to sympathetic stimulation partly reflect increased Ca2+ channel activity; i.e the cel- lular mechanisms mediating these effects appear to involve a cAMP-independent as well as a cAMP- dependent pathway. J. Clin. Invest. 103:1089–1097 (1999). Introduction that contradicts this position (14). The current model of The sympathetic nervous system plays a major role in the overexpressed Gsα presents a unique opportunity to rec- regulation of cardiovascular function under various oncile this controversy. To address these mechanistic stress conditions, such as hypotension, exercise, and the questions, it is necessary to study the contractile func- fight-or-flight reaction, by releasing catecholamines, tion of isolated myocytes, which has not been done pre- which, in turn, activate the β-adrenergic receptor– viously in the model of overexpressed Gsα (1–7). Fur- Gs–adenylyl cyclase (βAR-Gs-AC) pathway. To under- thermore, all prior studies have concentrated on stand the physiological and pathological mechanisms of inotropic function in vivo (2–5), neglecting another this cascade when the stimulation is chronic, murine important controlling mechanism, lusitropic function. models have been created by altering expression of com- The isolated myocyte technique lends itself to examina- ponents of the βAR signaling pathway (1–9). These mod- tion of that aspect of myocardial function as well. Final- els all demonstrated enhanced efficacy of the βAR-Gs- ly, it was important to conduct the present investigation AC signaling pathway (1–9). However, the chronic in adult as opposed to neonatal (7) myocytes, because (a) augmentation of βAR signaling in the model with over- it is possible to examine contractile and relaxation func- expression of cardiac Gsα leads to myocyte hypertrophy tion as well as Ca2+ channel activity in adult cells, and (b) and cardiomyopathy as these animals age (2, 4, 5), which it is well known that βAR-Gs-ΑC regulation differs differs from what has been reported in the other models markedly in neonatal animals (15–17). (8, 9). Another controversial issue is whether Gsα can The first goal of this study was to investigate the regu- alter L-type Ca2+ channel activity in a cAMP-PKA–inde- lation of isolated left ventricular (LV) myocyte contrac- pendent manner. Prior studies exist supporting such a tility by the βAR-Gs-AC pathway and the extent to which mechanism in vitro (10–13), although there is another myocyte contractile function is altered by overexpression The Journal of Clinical Investigation | April 1999 | Volume 103 | Number 7 1089 cose, and 5 HEPES (pH 7.4). The aorta was cannulated with a blunt-tip needle (20 gauge) on a perfusion apparatus. The heart was perfused for 3 min with Tyrode’s solution and then per- fused for 18 min with Tyrode’s solution with 2% FCS (Sigma Chemical Co., St. Louis, Missouri, USA) and 75 U/ml each of collagenase 1 and 2 (Worthington Biochemical, Freehold, New Jersey, USA) at 37°C. All solutions were continuously bubbled with 95% O2 and 5% CO2 at 37°C. Isolated myocytes were stored in Tyrode’s solution with 2% FCS and 10% BSA (Fraction V; Sigma Chemical Co.) before the experiment. Myocytes were stored at room temperature, and mechanical studies were com- pleted within 3 h after isolation to minimize deterioration due to prolonged storage of cells. Whether the mice were transgenic was blinded until the results of the studies were completed. Measurement of contractile and relaxation function. Myocytes were transferred to a warmed (37°C) and continuously perfused cell chamber located on an inverted microscope stage (Nikon Inc., Melville, New York, USA). The chamber was perfused with phys- iological buffer containing (in mmol/l): 120 NaCl, 2.6 KCl, 1.2 MgCl2, 1.2 KH2PO4, 11 glucose, 5 HEPES, 25 NaHCO3, 2 tau- rine, 1 pyruvate, and 1 CaCl2. Myocyte contraction was induced at 1 Hz by platinum field electrodes that were placed in the cell chamber and attached to a stimulator (S48; Grass Instrument Co., Quincy, Massachusetts, USA). Cell images were continu- ously monitored through a ×40 objective lens (Nikon Inc.) and transmitted to a charge-coupled device (CCD) video camera (TM-640; Pulnix, Mountain View, California, USA). The output from the CCD camera was displayed on a video monitor (PVM- Figure 1 135; Sony, New York, New York, USA). Myocyte length was Superimposed representative length (a) and Ca2+ transient (b) recordings α measured using a video motion edge detector (VED103; Cres- from a WT myocyte (thin line) and Gs -overexpressed myocyte (thick line). cent Electronics, Sandy, Utah, USA), and the data were acquired Neither myocyte contractile function nor systolic fura-2 signaling was at 240 images per second. Myocyte dimensions were calibrated affected in overexpressed Gsα myocytes. However, the recovery in late diastole was faster in Gsα, as noted by the time to 70% recovery of relax- ation (circles on tracings). WT, wild-type. of cardiac Gsα, as this approach will provide an assess- ment of intrinsic contractile function independent of the extracellular matrix and hemodynamic and neuro- hormonal effects. As part of this goal, it was important to determine whether lusitropic function was affected in a fashion parallel to inotropic function in the isolated myocytes. Once it was determined that lusitropic func- tion was altered at baseline both in isolated myocytes and in vivo, the mechanism was investigated by measur- ing baseline cAMP and phospholamban phosphoryla- tion. The next goal of this study was to determine whether the mechanism for the enhanced effects in response to βAR stimulation involved an action on the Ca2+ channel, potentially independent of cAMP. This was accomplished using a dual approach. First, Ca2+ channel function was assessed directly using patch-clamp tech- niques. Second, the effects of βAR stimulation were examined after the cAMP pathway was blocked with Rp- cAMP, an inhibitor of protein kinase A (PKA), which should abolish the enhanced inotropic effects induced by βAR stimulation of AC via Gs.
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