Dynamic and differential changes in myocardial and plasma endothelin in patients undergoing cardiopulmonary bypass

Multani, Marlina M.; Ikonomidis, John S.; Kim, Peter Y.; Miller, Elizabeth A.; Payne, Kim; Mukherjee, Rupak; Dorman, B. Hugh; Spinale, Francis G.

doi:10.1016/j.jtcvs.2004.07.018

Cited by 19 publications

(27 citation statements)

References 27 publications

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“…12,15,20 Elegant studies by Spinale et al have demonstrated a 4-fold increase in myocardial interstitial ET-1 levels after cardiopulmonary bypass. 21 However, even at peak levels postoperatively, myocardial ET-1 levels were only 50 fmol/L and in plasma these levels were Ͻ20 fmol/L. At doses of 100 pmol/L, we observed no effect of ET-1 on cellular NO …”

Section: Effect Of Et-1 On No Productioncontrasting

confidence: 53%

Elevated Endothelin-1 Levels Impair Nitric Oxide Homeostasis Through a PKC-Dependent Pathway

et al. 2006

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Background-Endothelin-1 (ET-1) plays an important role in the maintenance of vascular tone and pathological states such as ischemia/reperfusion (I/R) injury, coronary vasospasm, and cardiac allograft vasculopathy. We assessed the effects of elevated ET-1 levels as seen after I/R to determine if ET-1 modulates nitric oxide (NO) production via the translocation of specific protein kinase C (PKC) isoforms. Methods and Results-Human saphenous vein endothelial cells (HSVECs) (nϭ8) were incubated with ET-1 or phosphate-buffered saline (PBS) for 24 hours. NO production was determined in the supernatant by measuring nitrate/nitrite levels. Protein expression of endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), caveolin-1 and PKC were determined. Lastly, PKC translocation and activity were assessed after exposure to the drug of interest. HSVECs exposed to ET-1 displayed decreased NO production. PKC inhibition reduced NO production, whereas PKC activation increased production. NO production was maintained when HSVECs exposed to ET-1 were treated with the PKC agonist, PMA. eNOS protein expression was reduced after ET-1 treatment. PKC inhibition also downregulated eNOS protein expression, whereas PMA upregulated expression. ET-1 exposure led to a significant increase in PKC␦ and PKC translocation compared with control, whereas translocation of PKC was inhibited. ET-1 exposure significantly reduced overall PKC activity compared with control. Conclusions-Our study demonstrates that high levels of ET-1 impair endothelial NO production via an isoform-specific PKC-mediated inhibition of eNOS expression. ET-1 antagonism with bosentan stimulates translocation of PKC and leads to increased PKC activity and NO production. ET-1 antagonism may provide a novel therapeutic strategy to improve vascular homeostasis.

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Section: Effect Of Et-1 On No Productioncontrasting

confidence: 53%

Elevated Endothelin-1 Levels Impair Nitric Oxide Homeostasis Through a PKC-Dependent Pathway

et al. 2006

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“…Inhibition of the classical PKC isoforms (without exogenous ET-1) during CA improved myocyte shortening from CA only values. Because past studies have provided evidence that ET-1 levels increase within the myocardial interstitium during cardiopulmonary bypass 4,16 and that myocytes can synthesize and release ET-1, 7 incubation of myocytes with CA may have likely resulted in ET-1 production and subsequent PKC activation. Nevertheless, concomitant inhibition of each of the classical PKC isoforms in the presence of exogenous ET-1 and CA resulted in a marked improvement in myocyte shortening when compared with CA only.…”

Section: Discussionmentioning

confidence: 99%

“…Transient left ventricular (LV) dysfunction occurs after CA 1 and is associated with increased levels of bioactive peptides, including the vasoactive peptide, endothelin-1 (ET-1). [2][3][4] Moreover, elevated ET-1 levels in patients during and after cardiac surgery requiring CA may contribute to a complex postoperative course. 3 Although the effects of ET-1 on LV pump function after CA are likely to be multifactorial, ET-1 has been demonstrated to modulate myocyte contractile function, [5][6][7] which in turn can influence LV function.…”

mentioning

confidence: 99%

Protein Kinase C Isoform Activation and Endothelin-1 Mediated Defects in Myocyte Contractility After Cardioplegic Arrest and Reperfusion

et al. 2006

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Background-Endothelin-1 (ET-1) is released after hyperkalemic cardioplegic arrest (CA) and reperfusion and may contribute to contractile dysfunction. ET-1 receptor transduction causes activation of protein kinase C (PKC) isoforms, which can cause differential intracellular events. The goal of this study was to determine which PKC isoforms contribute to myocyte contractile dysfunction with ET-1 and CA. Methods and Results-Percent shortening (PERSHORT) and the time to 50% relaxation (T50) were measured in porcine (n ϭ22) left ventricular myocytes, randomized (minimum: 30 cells/group) to normothermia: (cell media for 2 hours/37°C), and CA: (2 hours/4°C, 24 mEq K ϩ solution followed by reperfusion in cell media), ET-1/CA: (100 pM ET-1 during CA). Studies were performed in the presence and absence of PKC inhibitors (500 nM) against the classical (Beta-I, Beta-II, Gamma) and novel (Epsilon, Eta) isoforms (myocytes from a minimum of 3 pigs per inhibitor). CA reduced PERSHORT by Ϸ35% from normothermia (PϽ0.05), which was further reduced with ET-1. PKC-Beta-II or PKC-Gamma inhibition increased PERSHORT from ET-1/CA as well as CA only (PϽ0.05). CA prolonged T50 by Ϸ19% from normothermia (PϽ0.05) and was further prolonged with ET-1. Inhibition of the classical PKC isoforms reduced T50 from ET-1/CA (PϽ0.05). Inhibition of novel PKC isoforms did not yield similar effects on either PERSHORT or T50 with ET-1/CA. Conclusions-Inhibition of the classical PKC isoforms relieved the negative inotropic and lusitropic effects of ET-1 after CA. These findings provide mechanistic support for developing targeted inhibitory strategies with respect to ET-1 signaling and myocyte contractile dysfunction with cardioplegic arrest and reperfusion.

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“…Further research demonstrated that the myocardial ECM maintains alignment of myofibrils within the myocyte through a collagen-integrincytoskeleton-myofibril relation (50,132,254,365,367,395,398,441). In addition to a fibrillar collagen network, a basement membrane, proteoglycans, and glycosaminoglycans, the myocardial ECM contains a large reservoir of bioactive molecules (17,34,41,64,89,95,101,109,111,114,188,288,360,362,492). For example, it has been demonstrated that the concentration of bioactive signaling molecules such as angiotensin II (ANG II) and endothelin (ET)-1 are over 100-fold higher within the myocardial interstitium than in plasma (89,101,288,492).…”

Section: A Structure and Function Of The Myocardial Matrixmentioning

confidence: 99%

“…In addition to a fibrillar collagen network, a basement membrane, proteoglycans, and glycosaminoglycans, the myocardial ECM contains a large reservoir of bioactive molecules (17,34,41,64,89,95,101,109,111,114,188,288,360,362,492). For example, it has been demonstrated that the concentration of bioactive signaling molecules such as angiotensin II (ANG II) and endothelin (ET)-1 are over 100-fold higher within the myocardial interstitium than in plasma (89,101,288,492). Moreover, cytokine activation and signaling such as that for tumor necrosis factor-␣ (TNF) is highly compartmentalized within the myocardial interstitium (95,111).…”

Section: A Structure and Function Of The Myocardial Matrixmentioning

confidence: 99%

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

Spinale¹

2007

Physiological Reviews

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It is now becoming apparent that dynamic changes occur within the interstitium that directly contribute to adverse myocardial remodeling following myocardial infarction (MI), with hypertensive heart disease and with intrinsic myocardial disease such as cardiomyopathy. Furthermore, a family of matrix proteases, the matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs), has been recognized to play an important role in matrix remodeling in these cardiac disease states. The purpose of this review is fivefold: 1) to examine and redefine the myocardial matrix as a critical and dynamic entity with respect to the remodeling process encountered with MI, hypertension, or cardiomyopathic disease; 2) present the remarkable progress that has been made with respect to MMP/TIMP biology and how it relates to myocardial matrix remodeling; 3) to evaluate critical translational/clinical studies that have provided a cause-effect relationship between alterations in MMP/TIMP regulation and myocardial matrix remodeling; 4) to provide a critical review and analysis of current diagnostic, prognostic, and pharmacological approaches that utilized our basic understanding of MMP/TIMPs in the context of cardiac disease; and 5) most importantly, to dispel the historical belief that the myocardial matrix is a passive structure and supplant this belief that the regulation of matrix protease pathways such as the MMPs and TIMPs will likely yield a new avenue of diagnostic and therapeutic strategies for myocardial remodeling and the progression to heart failure.

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Dynamic and differential changes in myocardial and plasma endothelin in patients undergoing cardiopulmonary bypass

Cited by 19 publications

References 27 publications

Elevated Endothelin-1 Levels Impair Nitric Oxide Homeostasis Through a PKC-Dependent Pathway

Elevated Endothelin-1 Levels Impair Nitric Oxide Homeostasis Through a PKC-Dependent Pathway

Protein Kinase C Isoform Activation and Endothelin-1 Mediated Defects in Myocyte Contractility After Cardioplegic Arrest and Reperfusion

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

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