Abstract
Increasing evidence indicates that the enzyme creatine kinase (CK) is intimately involved in microvascular contractility. The mitochondrial isoenzyme catalyses phosphocreatine synthesis from ATP, while cytoplasmic CK, predominantly the BB isoenzyme in vascular tissue, is tightly bound near myosin ATPase, where it favours ATP production from phosphocreatine to metabolically support vascular contractility. However, the effect of CK gene inactivation on microvascular function is hitherto unknown. We studied functional and structural parameters of mesenteric resistance arteries isolated from 5 adult male mice lacking cytoplasmic BB-CK and ubiquitous mitochondrial CK (CK–/–) vs 6 sex/age-matched controls. Using a Mulvany Halpern myograph, we assessed the acute maximum contractile force with 125 mM K+ and 10–5 M norepinephrine, and the effect of two inhibitors, dinitrofluorobenzene, which inhibits phosphotransfer enzymes (0.1 μM), and the specific adenylate kinase inhibitor P1, P5-di(adenosine 5′) pentaphosphate (10–6 to 10–5 M). WT and CK–/– did not significantly differ in media thickness, vascular elasticity parameters, or acute maximum contractile force. CK–/– arteries displayed greater reduction in contractility after dinitrofluorobenzene 38%; vs 14% in WT; and after AK inhibition, 14% vs 5.5% in WT, and displayed abnormal mitochondria, with a partial loss of the inner membrane. Thus, CK–/– mice display a surprisingly mild phenotype in vascular dysfunction. However, the mitochondrial abnormalities and greater effect of inhibitors on contractility may reflect a compromised energy metabolism. In CK–/– mice, compensatory mechanisms salvage energy metabolism, as described for other CK knock-out models.
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Abbreviations
- AK:
-
Adenylate kinase
- CK:
-
Creatine kinase
- CK–/– KO:
-
BB-CK/uMt CK Knock out
- MM-CK:
-
Muscle type of CK
- BB-CK:
-
Brain type of CK
- MtCK:
-
Mitochondrial type of CK
- UMtCK:
-
Ubiquitous MtCK
- SMtCK:
-
Sarcomeric MtCK
- D100 :
-
The optimal radius for active tension, at 90% of the diameter of a passive vessel at a pressure of 100 mm Hg
- DMSO:
-
Dimethyl sulfoxide
- DNFB:
-
Di-nitro-fluorobenzene
- MLCK:
-
Myosin light chain kinase
- PCr:
-
Phosphocreatine
- PSS:
-
Physiological salt solution
- SNP:
-
Sodium nitroprusside
References
Bakker EN, Buus CL, Spaan JA, Perree J, Ganga A, Rolf TM, Sorop O, Bramsen LH, Mulvany MJ, Vanbavel E (2005) Small artery remodeling depends on tissue-type transglutaminase. Circ Res 96(1):119–126
Brewster LM (2018) Creatine kinase, energy reserve, and hypertension: from bench to bedside. Ann Transl Med 6:292
Brewster LM, Clark JF, van Montfrans GA (2000) Is greater tissue activity of creatine kinase the genetic factor increasing hypertension risk in black people of sub-Saharan African descent? J Hypertens 18:1537–1544
Brewster LM, Mairuhu G, Bindraban NR, Koopmans RP, Clark JF, van Montfrans GA (2006) Creatine kinase activity is associated with blood pressure. Circulation 114:2034–2039
Brewster LM, Van Montfrans GA (2010) Calcium channel blocker therapy in black hypertensive patients. Am J Hypertens 23:218–218
Brewster LM, van Montfrans GA, Luke A, Adeyemo A, Kramer H, Forrester T, Cooper RS (2004) Response: blood pressure, resting energy expenditure, and creatine kinase activity. Hypertension 44:e6–e6
Clark JF (1994) The creatine kinase system in smooth muscle. Mol Cell Biochem 133:221–232
Clark JF, Pyne-Geithman G (2005) Vascular smooth muscle function: the physiology and pathology of vasoconstriction. Pathophysiology 12:35–45
De Groof A, Smeets B, Groot Koerkamp M, Mul A, Janssen E, Tabak H, Wieringa B (2001) Changes in mRNA expression profile underlie phenotypic adaptations in creatine kinase-deficient muscles. FEBS Lett 506:73–78
Decking UK, Alves C, Wallimann T, Wyss M, Jr S (2001) Functional aspects of creatine kinase isoenzymes in endothelial cells. Am J Physiol 281:C320–C328
Dzeja PP, Terzic A (2003) Phosphotransfer networks and cellular energetics. J Exp Biol 206:2039–2047
Dzeja P, Terzic A (2009) Adenylate kinase and AMP signaling networks: metabolic monitoring, signal communication and body energy sensing. Int J Mol Sci 10:1729–1772
Dzeja PP, Terzic A, Wieringa B (2004) Phosphotransfer dynamics in skeletal muscle from creatine kinase gene-deleted mice. Mol Cell Biochem 256:13–27
Dzeja PP, Vitkevicius KT, Redfield MM, Burnett JC, Terzic A (1999) Adenylate kinase–catalyzed phosphotransfer in the myocardium: increased contribution in heart failure. Circ Res 84:1137–1143
Dzeja PP, Zeleznikar RJ, Goldberg ND (1996) Suppression of creatine kinase-catalyzed phosphotransfer results in increased phosphoryl transfer by adenylate kinase in intact skeletal muscle. J Biol Chem 271:12847–12851
Gagliardi S, Atlante A, Passarella S (1997) A novel property of adenine nucleotides: Sensitivity to helium-neon laser in mitochondrial reactions. IUBMB Life 41:449–460
Ishida Y, Wyss M, Hemmer W, Wallimann T (1991) Identification of creatine kinase isoenzymes in the guinea-pig presence of mitochondrial creatine kinase in smooth muscle. FEBS Lett 283:37–43
Kaasik A, Veksler V, Boehm E, Novotova M, Ventura-Clapier R (2003) From energy store to energy flux: a study in creatine kinase-deficient fast skeletal muscle. FASEB J 17(6):708–710. https://doi.org/10.1096/fj.02-0684fje
Karamat FA, Oudman I, Ris-Stalpers C, Afink GB, Keijser R, Clark JF, van Montfrans GA, Brewsterl LM (2014) Resistance artery creatine kinase mRNA and blood pressure in humans. Hypertension 63(1):68–73
Karamat FA, Oudman I, Haan YC, van Kuilenburg AB, Leen R, Danser JA, Leijten FP, Ris-Stalpers C, van Montfrans GA, Clark JF, Brewsterl LM (2016) Creatine kinase inhibition lowers systemic arterial blood pressure in spontaneously hypertensive rats: a randomized controlled trial. J Hypertens 34(12):2418–2426
Karamat FA, Horjus DL, Haan YC, van der Woude L, Schaap MC, Oudman I, van Montfrans GA, Clark JF, Brewster LM (2017) The acute effect of beta-guanidinopropionic acid versus creatine or placebo in healthy men (ABC-Trial): a randomized controlled first-in-human trial. Br J Clin Pharmacol 83(12):2626–2635
Kuiper JW, Oerlemans FT, Fransen JA, Wieringa B (2008) Creatine kinase B deficient neurons exhibit an increased fraction of motile mitochondria. BMC Neurosci 9(1):73
Labella JJ, Daood MJ, Koretsky A, Roman BB, Sieck GC, Wieringa B, Watchko JF (1998) Absence of myofibrillar creatine kinase and diaphragm isometric function during repetitive activation. J Appl Physiol 84:1166–1173
Lenz H, Schmidt M, Welge V, Kueper T, Schlattner U, Wallimann T, Elsässer HP, Wittern KP, Wenck H, Staeb F, Blatt T (2007). Inhibition of cytosolic and mitochondrial creatine kinase by siRNA in HaCaT-and HeLaS3-cells affects cell viability and mitochondrial morphology. Mol Cell Biochem 306(1–2):153–162
Lorusso M, Marzo M, Gatti D, Papa S (1986) Effect of 2,4-dinitrofluorobenzene on theenzymatic properties of the b-c1 complex isolated from beef heart mitochondria. FEBSLett 195:298–302
Mayet J, Hughes A (2003) Cardiac and vascular pathophysiology in hypertension. Heart 89:1104–1109
Mulvany MJ (2018) Small artery remodeling and significance in the development of hypertension. Physiology. https://doi.org/10.1152/nips.01366.2001
Mulvany MJ, Halpern W (1977) Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res 41:19–26
Nakayama S, Clark JF (2003) Smooth muscle and NMR review: an overview of smooth muscle metabolism. Mol Cell Biochem 244:17–30
Nealon D (1985) Relative inhibition of human adenylate kinase and creatine kinase isoenzymes by adenosine 5'-monophosphate and diadenosine pentaphosphate. Clin Chem 31:333–334
Novotová M, Pavlovicová M, Veksler VI, Ventura-Clapier R, Zahradník I (2006) Ultrastructural remodeling of fast skeletal muscle fibers induced by invalidation of creatine kinase. Am J Physiol Cell Physiol 291:C1279–C1285
Nyborg N, Bevan JA (1988) Increased alpha-adrenergic receptor affinity in resistance vessels from hypertensive rats. Hypertension 11:635–638
Onda T, Uzawa K, Endo Y, Bukawa H, Yokoe H, Shibahara T, Tanzawa H (2006) Ubiquitous mitochondrial creatine kinase downregulated in oral squamous cell carcinoma. Br J Cancer 94(5):698–709
O'Sullivan W, Cohn M (1968) Magnetic resonance studies on inactivated forms of creatine kinase. J Biol Chem 243:2737–2744
Payne RM, Strauss AW (1994) Expression of the mitochondrial creatine kinase genes. Mol Cell Biochem 133:235–243
Schlattner U, Tokarska-Schlattner M, Wallimann T (2006) Mitochondrial creatine kinase in human health and disease. Biochim Biophys Acta 1762:164–180
Sperlágh B, Vizi ES (2007) Extracellular interconversion of nucleotides reveals an ecto-adenylate kinase activity in the rat hippocampus. Neurochem 32:1978–1989
Steeghs K, Oerlemans F, De Haan A, Heerschap A, Verdoodt L, De Bie M, Ruitenbeek W, Benders Ad, Jost C, van Deursen J, Tullson P, Terjung R, Jap P, Jacob W, Pette D, Wieringa Bé (1998) Cytoarchitectural and metabolic adaptations in muscles with mitochondrial and cytosolic creatine kinase deficiencies. Mol Cell Biochem 184(1–2):183–194
Steeghs K, Peters W, Bruckwilder M, Croes H, Van Alewijk D, Wieringa B (1995) Mouse ubiquitous mitochondrial creatine kinase: Gene organization and consequences from inactivation in mouse embryonic stem cells. DNA Cell Biol 14:539–553
Streijger F, Oerlemans F, Ellenbroek BA, Jost CR, Wieringa B, Van der Zee CE (2005) Structural and behavioural consequences of double deficiency for creatine kinases BCK and UbCKmit. Behav Brain Res 157:219–234
Streijger F, Pluk H, Oerlemans F, Beckers G, Bianco AC, Ribeiro MO, Wieringa Bé, Van der Zee CEEM (2009) Mice lacking brain-type creatine kinase activity show defective thermoregulation. Physiol Behav 97(1):76–86
Taherzadeh Z, Brewster LM, Van Montfrans GA, VanBavel E (2010) Function and structure of resistance vessels in black and white people. J Clin Hypertens 12:431–438
Taherzadeh Z, Karamat FA, Ankum WM, Clark JF, van Montfrans GA, van Bavel E, Brewster LM (2015) The effect of creatine kinase inhibition on contractile properties of human resistance arteries. Am J Hypertens 29:170–177
Takagi Y, Yasuhara T, Gomi K (2001) Creatine kinase and its isozymes. Rinsho Byori. Japan J Clin Pathol, 52–61
Tsung SH (1982) Total CK activity and isoenzyme patterns in normal and neoplastic tissue of gastrointestinal tract. J Clin Pathol 35:204–206
VanDerLijn P, Barrio JR, Leonard NJ (1979) Inhibition of adenylate kinase by P1-(lin-benzo-5'-adenosyl)-P4-(5'-adenosyl) tetraphosphate and P1-(lin-benzo-5'-adenosyl)-P5-(5'-adenosyl) pentaphosphate. Biochemistry 18:5557–5561
Veksler VI, Kuznetsov AV, Anflous K, Mateo P, Van Deursen J, Wieringa B, Ventura-Clapier R (1995) Muscle creatine kinase-deficient mice II. Cardiac and skeletal muscles exhibit tissue-specific adaptation of the mitochondrial function. J Biol Chem 270:19921–19929
Ventura-Clapier R, Kuznetsov AV, d'Albis A, van Deursen J, Wieringa B, Veksler VI (1995) Muscle creatine kinase-deficient mice. I. Alterations in myofibrillar function. J Biol Chem. 270(34):19914–19920
Ventura-Clapier R, Kaasik A, Veksler V (2004) Structural and functional adaptations of striated muscles to CK deficiency. Mol Cell Biochem 256:29–41
Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger H (1992) Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the'phosphocreatine circuit'for cellular energy homeostasis. Biochem J 281:21
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LMB is an inventor on patent WO/2012/138226 (filed). The other authors declare no conflict of interest.
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Taherzadeh, Z., van Montfrans, G.A., Van der Zee, C.E.E.M. et al. Structure and function of resistance arteries from BB-creatine kinase and ubiquitous Mt-creatine kinase double knockout mice. Amino Acids 52, 1033–1041 (2020). https://doi.org/10.1007/s00726-020-02872-x
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DOI: https://doi.org/10.1007/s00726-020-02872-x