Prostanoid-mediated inotropic responses are attenuated in failing human and rat ventricular myocardium

Riise, Jon; Nguyen, Charlene; Hussain, Rizwan I; Dahl, Christen P.; Ege, Maren S.; Osnes, Jan‐Bjørn; Skomedal, Tor; Sandnes, Dagny; Levy, Finn Olav; Krobert, Kurt A.

doi:10.1016/j.ejphar.2012.04.022

Cited by 9 publications

(19 citation statements)

References 31 publications

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“…This agrees with the study of Riise and collegues who reported prostanoid-mediated inotropic responses to be attenuated in the failing human myocardium. 32 The negative effect observed in this study was however only observed with high supra-clinical doses.…”

Section: A C C E P T E Dmentioning

confidence: 65%

Inotropic Effects of Prostacyclins on the Right Ventricle Are Abolished in Isolated Rat Hearts With Right-Ventricular Hypertrophy and Failure

Holmboe

Andersen

Johnsen

et al. 2017

Journal of Cardiovascular Pharmacology

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Background:Prostacyclin mimetics are vasodilatory agents used in the treatment of pulmonary arterial hypertension. The direct effects of prostanoids on right ventricular (RV) function are unknown.We aimed to investigate the direct effects of prostacyclin mimetics on RV function in hearts with and without RV hypertrophy and failure. Methods:Wistar rats were subjected to pulmonary trunk banding to induce compensated RV hypertrophy (n=32) or manifest RV failure (n=32). Rats without banding served as healthy controls (n=30).The hearts were excised and perfused in a Langendorff system and subjected to iloprost, treprostinil, epoprostenol or MRE-269 in increasing concentrations. The effect on RV function was evaluated using a balloon-tipped catheter inserted into the RV. Results:In control hearts iloprost, treprostinil and MRE-269, improved RV function. The effect was, however, absent in hearts with RV hypertrophy and failure. Treprostinil and MRE-269 even impaired RV function in hearts with manifest RV failure.Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. A C C E P T E D 3 Conclusion:Iloprost, treprostinil and MRE-269 improved RV function in the healthy rat heart. RV hypertrophy abolished the positive inotropic effect and in the failing right ventricle, MRE-269 and treprostinil impaired RV function. This may be related to changes in prostanoid receptor expression and reduced coronary flow reserve in the hypertrophic and failing right ventricle.

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Section: A C C E P T E Dmentioning

confidence: 65%

Inotropic Effects of Prostacyclins on the Right Ventricle Are Abolished in Isolated Rat Hearts With Right-Ventricular Hypertrophy and Failure

Holmboe

Andersen

Johnsen

et al. 2017

Journal of Cardiovascular Pharmacology

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“…The importance of constitutive RLC phosphorylation for normal cardiac performance is underscored by the reduction of RLC phosphorylation in human heart failure [44-47], and in animal models of myocardial infarction and pressure overload-induced heart failure [42, 48-54]. Pressure overload induced by transaortic constriction in wild-type mice reduced the extent of RLC phosphorylation by 40% and cardiac MLCK expression by 85% [54].…”

Section: Cardiac Contractile Protein System Overviewmentioning

confidence: 99%

“…Increased phosphorylation by overexpression of MLCK in the heart attenuates hypertrophic responses to stress [38, 54]. Human hearts in failure have reduced RLC phosphorylation [44-47]. …”

Section: Figurementioning

confidence: 99%

Role of myosin light chain phosphatase in cardiac physiology and pathophysiology

Chang

Kamm

Stull

2016

Journal of Molecular and Cellular Cardiology

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Maintenance of contractile performance of the heart is achieved in part by the constitutive 40% phosphorylation of myosin regulatory light chain (RLC) in sarcomeres. The importance of this extent of RLC phosphorylation for optimal cardiac performance becomes apparent when various mouse models and resultant phenotypes are compared. The absence or attenuation of RLC phosphorylation results in poor performance leading to heart failure, whereas increased RLC phosphorylation is associated with cardiac protection from stresses. Although information is limited, RLC phosphorylation appears compromised in human heart failure which is consistent with data from mouse studies. The extent of cardiac RLC phosphorylation is determined by the balanced activities of cardiac myosin light chain kinases and phosphatases, the regulatory mechanisms of which are now emerging. This review thusly focuses on kinases that may participate in phosphorylating RLC to make the substrate for cardiac myosin light chain phosphatases, in addition to providing perspectives on the family of myosin light chain phosphatases and involved signaling mechanisms. Because biochemical and physiological information about cardiac myosin light chain phosphatase is sparse, such studies represent an emerging area of investigation in health and disease.

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“…RLC phosphorylation is reduced in human heart failure (22)(23)(24)(25) and in heart failure animal models (8,26,27). Overexpression of MLCK in the heart increases the extent of RLC phosphorylation, which is associated with improved cardiac performance and attenuation of hypertrophic responses to stress (15,27).…”

mentioning

confidence: 97%

Cardiac myosin light chain is phosphorylated by Ca ²⁺ /calmodulin-dependent and -independent kinase activities

Chang

Mahajan

Knapp

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The well-known, muscle-specific smooth muscle myosin light chain kinase (MLCK) (smMLCK) and skeletal muscle MLCK (skMLCK) are dedicated protein kinases regulated by an autoregulatory segment C terminus of the catalytic core that blocks myosin regulatory light chain (RLC) binding and phosphorylation in the absence of Ca(2+)/calmodulin (CaM). Although it is known that a more recently discovered cardiac MLCK (cMLCK) is necessary for normal RLC phosphorylation in vivo and physiological cardiac performance, information on cMLCK biochemical properties are limited. We find that a fourth uncharacterized MLCK, MLCK4, is also expressed in cardiac muscle with high catalytic domain sequence similarity with other MLCKs but lacking an autoinhibitory segment. Its crystal structure shows the catalytic domain in its active conformation with a short C-terminal "pseudoregulatory helix" that cannot inhibit catalysis as a result of missing linker regions. MLCK4 has only Ca(2+)/CaM-independent activity with comparable Vmax and Km values for different RLCs. In contrast, the Vmax value of cMLCK is orders of magnitude lower than those of the other three MLCK family members, whereas its Km (RLC and ATP) and KCaM values are similar. In contrast to smMLCK and skMLCK, which lack activity in the absence of Ca(2+)/CaM, cMLCK has constitutive activity that is stimulated by Ca(2+)/CaM. Potential contributions of autoregulatory segment to cMLCK activity were analyzed with chimeras of skMLCK and cMLCK. The constitutive, low activity of cMLCK appears to be intrinsic to its catalytic core structure rather than an autoinhibitory segment. Thus, RLC phosphorylation in cardiac muscle may be regulated by two different protein kinases with distinct biochemical regulatory properties.

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Prostanoid-mediated inotropic responses are attenuated in failing human and rat ventricular myocardium

Cited by 9 publications

References 31 publications

Inotropic Effects of Prostacyclins on the Right Ventricle Are Abolished in Isolated Rat Hearts With Right-Ventricular Hypertrophy and Failure

Inotropic Effects of Prostacyclins on the Right Ventricle Are Abolished in Isolated Rat Hearts With Right-Ventricular Hypertrophy and Failure

Role of myosin light chain phosphatase in cardiac physiology and pathophysiology

Cardiac myosin light chain is phosphorylated by Ca ²⁺ /calmodulin-dependent and -independent kinase activities

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Prostanoid-mediated inotropic responses are attenuated in failing human and rat ventricular myocardium

Cited by 9 publications

References 31 publications

Inotropic Effects of Prostacyclins on the Right Ventricle Are Abolished in Isolated Rat Hearts With Right-Ventricular Hypertrophy and Failure

Inotropic Effects of Prostacyclins on the Right Ventricle Are Abolished in Isolated Rat Hearts With Right-Ventricular Hypertrophy and Failure

Role of myosin light chain phosphatase in cardiac physiology and pathophysiology

Cardiac myosin light chain is phosphorylated by Ca 2+ /calmodulin-dependent and -independent kinase activities

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Cardiac myosin light chain is phosphorylated by Ca ²⁺ /calmodulin-dependent and -independent kinase activities