ၡāāࢋ
( )
( ) ( ) ( CPU )
( )
ᙯᔣෟĈ͕҉ࡪ˧ጯੈཱི็ጱ ( Cardiac mechanotransduction )
͕۲̂ ( Cardiac hypertrophy ) ถᗓ̄ ( Calcium )
͕ࢦ ( Cardiac remodeling )
݈֏
ঽநّ͕҉۲̂ߏ˘ᓜԖ˯૱֍۞͕ঽ តĂົጱ͕҉නૺΑਕᅪᘣĂࠤҌౄјҕّ
͕ঽăೋّ͕ޠ̙ፋă͕აᄃ↢Ѫ1, 2ĄϤ ٺঽநّ͕҉۲̂ߏధк়͕ঽ۞ϲПᐍЯ
̄ĂЯѩ၆ٺ͕ࡊᗁर҃֏ĂтңᔖҺঽநّ
͕҉۲̂ߏ˘࣎࠹༊ࢦࢋ۞ኝᗟĄ
ѝд˘˝̱ѐĂ Meerson ඈˠಶ͕҉
۲̂۞࿅̶ࠎˬ࣎ล߱Ĉ൴णഇăᐺഇᄃ͕
აഇ3Ąᔵ͕҉۲̂۞ྮशֶᖞ̙ᕝצז
߿̼Ăҭߏ͕აഇݒــҡᐌ͕ވ۞ᕖ̂
ᄃ͕Ꮾณ۞ഴ͌ĄᔙШ͕ა۞࿅૱ᄃ
ࡪ̰ถᗓ̄۞ޮؠ4ᄃᗓ̄߹Ш5, 6צז̒ᕘѣ
̷۞ᙯܼĄ
ధкࣧЯົጱ͕۲̂ĂΒ߁ᑅ˧ٕट᎕
۞࿅ޘఈă҉̰ኳშకϨ ( sarcoplasmic reticu- l u m ) ۞ࡎតă͕҉ୟౄј۞ొ̶͕ຫ๋
ඈĄ̚Ăдᑅ˧࿅ޘఈ۞ଐڶ˭Ă͕۲̂
Էႊᐺ۞үϡĂΞͽഴ͕͌ጨٚצ۞ᑅ˧ᄃ উঈ۞ঐਈ7-9Ą˘ਠᄮࠎৠགྷវ୵ّ ( neurohu- moral ) ᄃ፟ୠّ ( mechanical ) Я̄д͕ࢦ۞
࿅Էႊᙯᔣّ۞֎ҒĂ፟̚ୠّЯ৵ጱ
Ԋొ፬৵۞̶کՀజෛࠎౄј͕۲̂۞Я
10ĄЯѩĂຐࢋၔغᒢྋ͕۲̂۞፟טซ҃ዋ ॡ̬ˢĂᑕАᒢྋ͕˧ጯੈཱི۞็ጱĄ
͕˧ጯੈཱི็ጱຍ͕҉ࡪઍീז፟ୠ
ّᑅ˧۞ត̼֭ઇͅᑕĂኜтќᒺ˧۞Լតă ᗓ̄πᏊ۞ԼតăࡪᛖүϡᄃૄЯ۞ܑனඈĄ˧
ጯੈཱི็ጱޢΞਕጱ͕҉۞۲ݓĂҭߏϠந
ّ۲ݓᄃঽநّ۲ݓጐგֹϡ࠹Т۞็ጱྮशĂ ݒົѣၟ̙Т۞ᓜԖޢڍ ( ဦ˘ )ĄЯѩտౣ
̦ᆃᇹ۞ੈཱིડҾ˞۰̪ߏϫ݈ܨ୬ᗃ۞ય ᗟĄГ۰ĂϤٺถᗓ̄፧ޘᄃ͕҉ࡪќᒺ˧̝
มѣ̷ᙯܼĂͷถᗓ̄࠹ᙯྮश࠹၆ٺ
ྮशдᘽநᑕϡ˯۞ࡁտྵࠎјሢĂώቔ͛ౢ˵
ࢦٺଣѩྮशĄ
˧ጯੈཱི็ጱྮश
ॲፂ Tavi д 2001 ѐ۞൴ܑ۞ტኢ11Ă͕
۞˧ጯੈཱི็ጱ࿅Ξͽజͧಔࠎ˘࣎ཝ΄
۞በቅᄃྋቅ۞࿅ ( ဦ˟ )Ą༊͕۞ఈᆧ ΐ۞ॡ࣏ ( າ۞΄ )Ă࣎ੈཱིᅮࢋజዋ༊۞
̶̄ઍീ ( ᔣሹᖼᛌ ) ֭གྷϤௐ˟৺็ጱۏኳ ( ᇴ Ҝੈཱི ) ็ᅍĂ̝ޢГϤ˭ഫ̶̄ ( CPU ) ઇͅ
ᑕ ( ྋቅᄃેҖ΄ )Ą࣎࿅ߏ˘࣎ტኑ ᗔ۞შྮĂڱϡಏ˘۞ੈཱི็ᅍրྋᛖć˵
Яѩͅߍ˞͕˧ጯੈཱི็ጱߏ˘࣎צזᚑአ ଠăᒖᒖ࠹љ۞րĄ
д࣎็ጱր̚ĂԧࣇΞͽপҾڦຍזถ ᗓ̄ٙԷႊ۞֎ҒĄ͕҉۞ќᒺ˧ۡତצזถ ᗓ̄፧ޘᇆᜩĂҭߏΩ˘͞ࢬถᗓ̄ώ֗˵ߏ˘
࣎ޝࢦࢋ۞˟৺ੈཱི็ᅍ۰ĂЯѩд˧ጯ็ጱր
̚ถᗓ̄Էႊ˞ᗕࢦ۞֎ҒĄ̙֭΄ˠຍγ
۞Ăд͕҉ࡪЯᑕ፟ୠᑅ˧Լតٙઇ۞ѝഇ
ͅᑕ̚Ăధкౌঘז˞дќᒺഇࡪ̰ถᗓ̄
፧ޘൺᇶ۞̿12( ဦˬ )Ą
˘ă˧ጯੈཱི۞ତќᄃ็ᅍĈ͕҉̚၆ٺૺ˧ୂ
ຏ۞̶̄ ( Stretch-sensitive molecular elements in cardiac myocytes ) ᄃௐ˟৺็ጱۏኳ
( second messengers )
ኢ͕҉˧ጯ็ጱրĂځពăࢦࢋă ݒ˵ᙱаඍ۞યᗟಶߏĈտౣ̦ᆃߏ͕۞ૺ
˧ຏצጡ ( stretch receptor )ĉ͕҉ࡪҬͼ̙ည
̰҅ͨࡪٕ۰ϩቲ۞ᛈᛇצጡ˘ᇹѣপ̼۞ૺ
˧צጡĂҭߏϫ݈ᄮࠎᔘߏѣߙֱ၆ૺ˧ୂຏ۞
̶̄፟טхдΞͽઍീ͕፟ୠᑅ˧۞Լតćι ࣇҌ͌Β߁˭ЕαĈ
( ˘ ) Ᏼፄّวᗓ఼̄ ( non selective cation channel )
͕҉ࡪ۞ᓂШ͔Ξͽ߿̼Ᏼፄّวᗓ
఼̄Ăౄјทᗓ̄ᄃถᗓ̄۞യˢĂѩ˟۰࠰
Ξጱถᗓ̄ҋ҉̰ኳშ ( sarcoplasmic reticulum )
۞ᛖٸĄ࣎፟טҌϫ݈ࠎͤإڱֹϡᘽந၁ រᙋ၁Ăҭߏдֹϡញჯϓࡪ ( fibroblast ) ۞ ࡁտ˯۞ቁពϯֱצזૺ˧߿̼۞ᗓ఼̄
( stretch-activated channel, SA channel ) ᄃࡪ
ߛ (т cytoskeleton, actin filament ) ࠹ాĂͷໂࠎ ဦ˘ĈϠநّ۲̂ᄃঽநّ۲̂Ą͕҉ࡪੵ˞ѣќ
ᒺͽଯજҕ୵ೈᒖ۞ۏநΑϡĂ˵ົ̙ᕝତќధ к፟ୠᄃ̼ጯੈཱིᄃಛᒖဩĶϹኘķĂֶ֭ፂ ᒖဩᅮՐ҃யϠԼតĄԼតΞͽ̶јዋᑕᄃεᏊ
ĂԼត۞ВТඕԊ૱ߏ͕҉۞۲̂Ą̚Ϡ நّ۲̂ߏЯᑕϠܜੈཱི۞˘ዋᑕҖࠎĂঽந
ّ۲̂ߏࢬ၆ᑅ˧ੈཱི۞εᏊͅᑕĄ҃ੈཱི
˭ഫ็ᅍ۞ྮशــ࠹̢ࢦᝑĂזϫ݈ࠎͤԧࣇ
̪ᖞ̙ߏӎѣপ۞ੈཱིٕྮशΞͽ˘
г͔Ϡநّ۲ٕ̂۰ঽநّ۲̂Ă˵̙ߏ ӎ࿅к۞Ϡܜੈཱིົጱঽநّ۲̂ĄТᇹ۞Ă ዋᑕᄃεᏊտౣߏాᜈЍᙉٕ۰ߏϲְІĂ
Ϻߏإޞᗃ۞યᗟĄ(࣒ԼҋĈ Hypertrophy as a Therapeutic Target 80)
Ξਕߏአଠ۞˘ᒖ13Ą
( ˟ ) ќᒺಏҜ ( contractile element )
ќᒺಏҜΞͽᄲߏϫ݈צזᇃھࡁտ۞ૺ
˧ઍീጡĄԧࣇٙሢۢ۞ڱᜋҹ- Ϋ྿ڒؠޠ ( Frank-Starling law )ͅߍ˞༊͕҉۞፟ୠّᑅ˧
ᆧΐॡќᒺ˧ಶົᆧૻ۞ன෪ćι۞јЯಶΞͽ ϡќᒺಏҜࢬ၆፟ୠّᑅ˧ॡ۞តֽ̼ྋᛖĈ
༊͕፟ୠّᑅ˧˯̿ॡĂ҉̈༼ܜޘົ
ဦ˟Ĉ͕҉ࡪ˧ጯ็ጱ۞ྮशΞͽజͧಔࠎཝ΄
۞በቅᄃྋቅ۞࿅Ą
( a ) በቅĈтТᔣሹԧࣇԓ୕ઇ۞જүᖼೱј
ཝᄮΞ۞ܫཱིĂ၆ૺ˧ୂຏ۞צጡ ( stretch- activated-channels, SA-channels )ă҉ញჯඈ ώ֗˵Էႊ˞Ķᔣሹķ۞֎ҒĂઍീז͕ఈ
۞Լត ( ̙Т۞Ķ΄ķ) ޢᖼೱјΞͽд
ࡪ̰็ᅍ۞ੈཱིĄ
( b ) ቅ็ᅍĈညߏёΞͽᖼೱј 0 ᄃ 1 ۞ᇴ Ҝੈཱིซˢ C P U Ă˟৺ੈཱི็ᅍ۰˵Էႊ
ĶᇴҜੈཱིķ۞֎ҒĂΞͽࣧώ۞ᒖဩੈཱིͽ າ۞ԛёдࡪ̚็ᅍ˭ΝĄ
( c ) ੈिྋቅĈ CPU פז˞ᇴҜੈཱི̝ޢົࢦ າᖼೱј΄Ąࡪତќז˞ੈिĂ˵ົயϠኜ т҉҇ќᒺăᒤᅕ ᄃΝᒤᅕ ߿̼ඈඈͅᑕĄ ( d ) ( Β߁ᛖ ANP ă BNP ٕϠܜЯ̄ඈ ) ֽഴ ᅅ݈ఈֹٕ͕҉ࡪត۲ݓăќᒺ˧Հૻć
࣎Վូ˵ѣΞਕঘזᖼᐂЯ̄۞߿̼Ą ( e )Αਕε૱Ĉѣֱёົᆧซүຽր۞Α ϡĂҭߏ˵ѣֱёᄃүຽր̙࠹टĂٺߏౄ
јཝ༊፟Ą͕҉ࡪтڍତќז̙։۞ੈཱིĂ
ޢ˵ົጱঽநّ͕۲̂ࠤҌౄј͕҉ࡪ
ࣟ˸ă͕აĄ
( ࣒ԼҋĈ Cardiac mechanotransduction: from sensing to disease and treatment11.)
ဦˬĈ͕҉˧ጯੈཱི็ጱٙঘ۞̶̄፟טĄ
͕҉ࡪ̚ѣ˘ֱઍീૺ˧۞፟טĂтצזૺ˧
߿̼۞Ᏼፄّวᗓ఼̄ ( SA channel )ăќ ᒺಏҜ ( actin-myosin )ăࡪᄃૄኳ۞Ϲ̢үϡ ( integrin ) ඈĄ͕҉ࡪ˵ົצזࡪ۞ᇆ ᜩĂтញჯϓࡪٕ̰ϩࡪඈ̶ک۞ҕგќᒺ
৵̰̈́ϩ৵Ąֱੈཱིົ͔ࡪ̰˟৺็ጱۏ ኳ۞˯̿Ăࢦࢋ۞ಶߏถᗓ̄ྮशᄃ ILK ߿̼
ޢ͔൴۞˘ాҚᒤᅕ̼ͅᑕĄ̚Ăถᗓ̄̿
ޢᄃ calmodulin ඕЪĂԛј̝ኑЪۏΞͽ߿̼
˭ഫிкᅔ৵ĂΒ߁ᒤᅕ CaMKIIᄃΝᒤᅕ calcineurinĄΩ˘͞ࢬĂ AngII ᄃ ET-1 ۞үϡ
ົ߿̼ PLC Ăซˢ PKC pathway Ă֭யϠ IP3 ᄃ҉̰ኳშ˯۞ IP3 צጡඕЪĄ̙გߏࣹ˘ੈ
ཱི็ጱྮशĂكѩ̝มౌົѣᓑЪ۞ड़ڍĂࣇ
ޢ˵ೀͼౌົүϡдࡪ८̰Ăአଠኜт GA- TA-4ă NF-AT ᄃ MEF2 ඈᖼᐂૄЯĂౄјၙّ
۞ᐺĄ
SA channel: stretch-activated channelצזૺ˧
߿̼۞ᗓ఼̄Ă ILK: integrin-linked kinase, AngII: angiotensin IIҕგќᒺ৵Ă ET-1: en- dothelin-1̰ϩ৵Ă ETAR: endothelin-1 recep- tor̰ϩ৵צጡĂ NaCaX: ทถϹೱᑒĂ PLC:
phospholipase C, IP3: inositol1,4,5-triphosphate, IP3R: IP3 receptor, DAG: diacylglycerol, PKC:
protein kinase C, SR: sarcoplasmic reticulum҉
̰ኳშĂ CaM: calmodulin, Ca2+CaM: complex of Ca2+and calmodulin, CaMKII: CaM-kinase II, MAPK: mitogen-activated protein kinase, MEF2:
myocyte enhancer-binding factor 2
(࣒ԼҋĈ Cardiac mechanotransduction: from sensing to disease and treatment11.)
ԼតĂጱញჯม۞ԛតĂЯ҃ΡะՀкүϡ ಏҜ ( actin-myosin ) ۞Ϲ̢үϡćΩ˘͞ࢬĂ҉
̈༼ܜޘᆧΐॡĂќᒺಏҜ˯యᄃถᗓ̄ඕЪ
۞צጡ troponin C ( TnC ) ၆ถᗓ̄۞Ꮠ˧˵ົ
ᆧΐ14ĂЯѩӈֹд࠹Т۞ถᗓ̄፧ޘ˭Ă͕҉
˵ົѣྵָ۞ќᒺ˧Ąֹϡ levosimendan15ᙷ ᘽۏΞͽឰࡪ၆ٺถᗓ̄ՀࠎୂຏĂЯѩΞͽ д࠹Тถᗓ̄፧ޘ˭ᆧΐ҉҇ќᒺ˧Ăүϡ፟ט ᙷҬٺૺ˧၆ٺ TnC ۞ᇆᜩĄ
( ˬ ) ࡪᄃૄኳ۞Ϲ̢үϡ ( cell-matrix in- teraction )
д࣎፟ט̚ࢦࢋ۞̶̄ಶߏ integrin Ą Integrinߏ˘ቯצጡĂᄃధкၹјࡪߛ۞
̶̄࠹ాĂ༊͕҉ࡪצזٛԵॡ integrin ಶΞ ͽઍീזᒖဩ۞Լត֭ੈཱི็ᅍ˭Ν16Ą
( α ) ࡪ۞ᇆᜩ
д͕҉ࡪצזૺ˧۞ТॡĂܢܕ۞ࡪ˵
ົצזᇆᜩ̶҃ک˘ֱҋک৵ ( autocrine factors ) ᄃک৵ ( paracrine factors )Ăซ҃߿̼͕҉ࡪ
̚Ξਕ۞็ጱश17, 18Ą̚Ăញჯϓࡪ
ົ̶کҕგќᒺ৵ ( angiotensin II, AngII )Ă̰҃
ϩࡪົ̶ک̰ϩ৵ ( endothelin-1, ET-1 )Ă
۰၆ٺ͕҉ࡪౌѣҌࠎஎᅈ۞ᇆᜩĄ
ET-1ᄃצጡ ( ETA receptor ) ඕЪޢົ߿̼
protein kinase C ( PKC ) ྮशĂޢጱท୰Ϲೱ ᑒ۞ᒤᅕ̼Ăֹࡪ̰ทᗓ̄፧ޘᄃ pH ࣃ
࠰˯̿19Ąࠎ˞ଵкዶ۞ทᗓ̄ĂทถϹೱᑒ
߿ّٺߏᆧΐĂֹࡪ̰ถᗓ̄፧ޘ೩Ą ET-1˵ົ߿̼ IP-3 צጡ (inositol 1,4,5-triphosphate receptor )Ăֹถᗓ̄ҋ҉̰ኳშ۞ᛖٸᆧΐĄ
̙࿅ޢ۰д̙Т͕҉ࡪүϡ̂̈˵̙ТĂЯࠎ
͕ٗࡪ͕ͧވࡪѣՀк۞ IP-3 צጡ20Ą
˟ă˧ጯੈཱི۞ྋቅĈ
CalmodulinᄃᕆЪ৵࠹ᙯᒤᅕ ( integrin- linked kinase ) ۞˭ഫྮश
Яࠎ҉҇ૺ˧۞Լតົጱถᗓ̄̈́˟
৺็ጱۏኳ፧ޘ۞˯̿ ( ቅ )ĂЯѩᅮࢋপঅ
۞ੈिצጡֽྋᛖ˯಼̿ޘᄃᐛதܑٙ۞ຍཌྷ ( ྋቅ )Ąͽ˭ಶϡถᗓ̄ྮशࠎܑĂઇ˘࣎ᖎ ಏ۞ᄲځĈ
( ˘ ) ถᗓ̄ྮश
Calmodulin ( CaM ) ߏ࣎Վូ̚ܧ૱ࢦࢋ۞
̶̄ĂιΞͽᄃถᗓ̄ඕЪԛјኑЪۏĂᚶᜈ߿
̼˭ഫ۞ிкᅔ৵Ą࿅ޘܑன CaM ۞ૄЯᖼ ത̈ဂटٽѣ͕۲̂۞યᗟ21Ă҃ו፬ϥݭඪ
˯ཛྷ৵צጡ͔۞͕۲̂Ξͽֹϡ CaM ۞
ԩ W 7 ֽᔖҺ2 2Ąᄃѩྮश࠹ᙯ۞፟ᖼΒ ߁Ĉ
1.CaM-kinase II ( CaMKII )Ĉд calmodulin ߿̼
۞ᅔ৵྆జࡁտၔغ۞˘࣎Ąι۞Αਕк ᇹĂΞͽአଠధкᄃถᗓ̄࠹ᙯ۞కϨĂ˵Яѩ ၆ٺถᗓ̄۞ੈཱི็ᅍྮशѣ࠹༊எᅈ۞ᇆᜩ23Ą
тТ݈Ăถᗓ̙̄Ϊߏ˘࣎ᄃ҉҇ќᒺ˧
ѣᙯ۞ۏኳĂιώ֗˵ߏ˘࣎ࢦࢋ۞Ѩ৺ੈཱི็
ᅍ۰Ăд̙Т۞ࡪă̙Т۞ੈཱི็ᅍྮश̚ౌ
Էႊ˞ᙯᔣ۞֎ҒĄЯѩĂֹϡ CaMKII Ժט
۞ࡁտտົ࿃ז۞ᐚдٺĈԧࣇଂۢԺ ט CaMKII ۞ඕڍߏտౣߏ੫၆ૺ˧ͅᑕᔘߏЯ ࠎ̒ᕘ˞ถᗓ̄۞ੈཱི็ጱĄ
2.CalcineurinĈ̙ͤᒤᅕ Ă calmodulin ˵
߿̼Νᒤᅕ Ă c a l c i n e u r i n ಶߏ˘ּĄ Calcineurinߏాඕࡪ̰ถᗓ̄็ጱྮशᄃ͕҉
۲̝̂ม۞˘࣎ࢦࢋሇĂ࿅ޘܑன calcineurin
۞ૄЯᖼത̈ဂົጱ͕҉۲̂24Ą҃дֹϡ ᒖࡪី A ( cyclosporin A ) ̈́ FK506 ඈ calcineurin Ժט۞၁រݒڱז˘۞ඕڍ24-28Ą
3.Ĉ҃Ăд࣎ր྆Ă˵ѣ̙ᅮࢋ
གྷ࿅ถᗓ̄۞ੈཱི็ᅍྮशĄ̙გߏҕგૺ˧৵
ٕ۰ ET-1 ۞үϡౌΞͽ߿̼ PLC (load-related phospholipase C )Ă҃ PKC ಶߏ PLC ࢦࢋ۞˭ഫ
ੈཱི็ᅍྮश̝˘ĄдૄЯᖼത̈ဂĂ࿅ޘ߿̼
۞ Gq కϨ29( PLC˯ഫ ) ᄃ PKC ۞࿅ޘܑன30, 31ౌ
ົౄј͕҉۲̂Ą PKC ۞߿ّᄃ MAPK ( mito- gen-activated protein kinase ) ྮशѣᙯć MAPK ߏ
˘ᄃ DNA ඕЪ۞కϨĂ MAPK ۞߿̼Ξͽᆧ ΐপؠૄЯ۞ᖼᐂăЯ҃ጱ͕҉۲̂32Ą
ֱ̙Т۞ੈཱི็ጱྮशكѩ̝ม၁ౌѣᓑЪ
۞ड़ڍĂԺט CaMKII ٕ۰ calcineurin ˵ౌΞͽ
֨ͤ ET ͔۞͕҉۲̂33ć҃ calcineurin ˵Ξ
ܳซ PKC ᄃ c-JUN N-terminal kinase ( JNK ) д͕
҉ࡪ̚۞߿̼҃มତܳซ͕҉۲̂۞யϠ34Ą ( ˟ ) Integrin ྮश
Integrinдࡪኳ̚۞ԍბాତ integrin-linked kinase ( ILK )Ăߏ˘ᇃھܑன۞ serine/threo- nine protein kinaseĂүࠎሇాඕࡪ/ૄኳϹ̢
ү ϡ ᄃ ͕ ࡪ ߛ ࢦ ੈ ཱི ۞ ็ ᅍ3 5 - 3 7Ą ILKд͕҉ࡪܑனณĂ҃ͷд҉̈༼̚Ξ ͽԱז I L K ᄃకϨኳٙԛј۞ኑЪវ3 7Ą ILKд͕҉˧ጯ็ጱ࿅̚Էႊ࠹༊ࢦࢋ۞֎
ҒĂҭЯࠎϫ݈дᓜԖᑕϡྵ͌Ă߇ώ̙͛Г
ኢĄ
ˬăତќੈिޢ۞ዋᑕᄃᐺҖࠎ
1.ൺഇĈӀϡϠநа㒝үϡഴ͕͌ఈ
͕˧ጯੈཱི็ጱ۞ࢋϫ۞ಶߏࠎ˞аೇ
ࣧώېၗăֹᒖဩჯޮؠĄЯѩ߿̼ৠགྷّᄃ វ୵ّ፟טͽᆧΐ͕ќᒺ˧ăഴҲҕҖજ˧
ఈ˜ߏ˧ጯੈཱི็ጱ۞˘࣎ࢦࢋ۞ዋᑕ፟ᖼĄ ( 1 ).͕፬৵ ( cardiac hormone )
༊ ͕ ۞ ҉ ҇ జ ٛ ᇣ ॡ Ă ͕ ٗ Ӏ ท ፬ ৵ ( ANP )ᄃ͕ވӀท፬৵ ( BNP ) ົЧҋϤ͕ٗᄃ
͕ވЪјăᛖٸ3 8Ąֱ፬৵д͕ă̰ϩ
ࡪăඪ̈გࡪౌѣצጡĂΞͽ߿̼ guanylate cyclaseĂጱ cGMP ۞̿ĂயϠ۞Ϡநड़ڍ ኜтᆧΐඪ̈࿅ᕭதăᆧΐඪทଵณă
ಛᖐҕგᕖૺăഴ͌Ϲຏৠགྷրᄃ R A S ( rennin-angiotensin system ) ۞߿̼ඈ39Ăౌߏࠎ
˞ഴ͕͌۞݈ăޢఈᄃࢫҲ͕ਈউณĄ ( 2 ).˙ݭඪ˯ཛྷ৵צጡ ( ɘ adrenoreceptor )
ࢋঘ̈́୧ྮशĈ PKA ࠹ᙯྮशᄃถᗓ
̄ୂຏྮश۞߿̼Ą P K A ˘͞ࢬΞͽᒤᅕ̼ L ݭถᗓ఼̄ĂֹજүҜॡถᗓ̄۞യˢᆧ ΐćΩ˘͞ࢬߏᒤᅕ̼ phospholamban Ăֹ
҉̰ኳშ˯۞ Ca2+-ATPase ( SERCA ) ߿ّ˯̿Ă ЯѩΞͽԣిаќᛖ۞ถᗓ̄Ąɘצጡ߿̼
ޢĂ˭ഫถᗓ่̙̄ᛖٸณᆧΐĂᛖٸᐛத˵
ᆧΐĂֹᚭ༼˯۞༼ޠࡪ൴ੈཱི۞ᐛதᆧ ΐĄ
( 3 ).ϠܜܳซЯ̄ ( growth promoting factor ) ϠܜܳซЯ̄Ξͽૻ̼˧ጯੈཱི็ጱώ֗
ֽ۞ϠܜੈཱིĂЯѩдѝഇֱҋک৵ٕک৵ ѣᐺ۞ΑਕĂҭߏܜ˳˭ֽĂֱᐺΞਕ
ົጱѣच۞͕҉۲̂ĄֱϠܜЯ̄̚ࢦࢋ
۞࣎ಶߏ݈͛അགྷ೩̈́۞ AngII17, 40ᄃ ET-141, 42Ă
ࣇكѩ˵ѣᓑЪ۞үϡ19Ą̙࿅˘ֱֹϡԺט
ᄃૄЯᖼത̈ဂ۞၁រݒ൴னࣇᔵࢦࢋݒ ܧυࢋ43ćጐგтѩĂࣇ̪ᖞ̙εࠎᘽۏฟ൴
۞։рᇾ۞Ą
2.ܜഇĈ࿅ૄЯᖼᐂ
݈۞ྋቅ࿅̚߿̼۞ᒤᅕ ᄃΝ ᒤᅕ ( т݈͛೩̈́۞ CaMKII, calcineurin ඈ )Ă
ޢــౌົአଠధкᖼᐂЯ̄ĄֱᖼᐂЯ̄
ᇾ۞۞ૄЯኜт transcriptional enhancer factor 1 ( TEF-1 )ă activating protein 1 ( AP-1 ) ̈́ serum re- sponse element ( SRE ) ඈĂдາϠ͕҉ࡪ in vitro۞၁រ̚ౌԷႊࢦࢋ۞֎Ғ44ć̙࿅дј ˠវ̰۞ঽந፟ט̚Էႊ۞֎Ғݒ̪ᖞϏځĄͽ
˭ߏ˘ֱࢦࢋ۞ᖼᐂЯ̄Ĉ ( 1 ).GATA-4
ߏ˘ӣѣዘ͘ ( zinc finger ) ۞ᖼᐂЯ
̄ćአଠ BNP ă ANP ăɘ-myosin heavy chain ( ɘ-MHC ) ᄃ TnC ඈᄃ۲̂࠹ᙯ۞ૄЯ45Ăҭߏ
˵አଠᄃϒ૱ዋᑕҖࠎѣᙯ۞ૄЯĂтทถϹೱ ᑒ46Ą
( 2 ).NF-AT
CalcineurinΞͽ NF-AT Νᒤᅕ̼Ăֹ
NF-ATซˢ८̰Ă֭ܳซᄃ AP-1, GATA-4 ٕ
˘ֱᖼᐂЯ̄ DNA ۞ඕЪ47Ą
( 3 ).Myocyte enhancer-binding factor 2 ( MEF2 ) צז CaMKIV ۞߿̼48Ăᄃ GATA-4 ѣᓑЪ
۞ड़ڍ49Ą
ҕҖજ˧ጯ۞Լត͔۞͕҉۲̂૱ҡᐌ
ኑᗔ۞ૄЯአଠត̼50, 51ćֱត̼ѣ۞֝ి҃
ൺᇶ ( ൴Ϡд˘࣎̈ॡ̝̰ )Ăтߙֱ८ᖼᐂЯ
ٕ̄ BNP ۞ૄЯಶᛳٺϲӈ-ѝഇૄЯ ( immedi- ate-early genes )52ćѣֱߏྵࠎቤၙ ( ൴Ϡд˩
˟Ҍ˟˩α̈ॡ̝̰ )Ăညߙֱࡩॡഇܑன۞
ૄЯт ANP ăᐪ҉۞ɗ-actin ᄃɘ-MHC ඈΞ ਕࢦາܑனĂΩγߙֱቯకϨт SERCA ᄃ˙ݭ ඪ˯ཛྷ৵צጡ۞ૄЯܑனณົഴ͌Ą҃˘ֱᄃ ਕณᔁѣᙯ۞ૄЯϺצአଠĂֹܳࡪਕૉՀ ѣड़гӀϡਕณ51Ą
ࣃڦຍ۞ߏĂᖼᐂአଠТᇹ˵൴Ϡдྻજ
͔۞Ϡநّ͕҉۲̂ ( ϺӈĶ ྻજࣶ۞͕
( athlete's heart )ķ)ćѩॡᆧΐ۞፟ୠّᑅ˧̙ҭ
ᆧซ͕ΑਕĂ˵ܳซઉ۞͕҉јܜĄ αăΑਕεአĈዋᑕ̙։ᄃᐺεୀ۞ඕԊ
̙ТٺϠநّ۞͕҉۲̂Ăঽநّ۞͕҉۲
̂ົֹ͕Αਕεአć̙ҭڱዋ༊නૺăќ
ᒺតၙ51, 53Ă˵ᇆᜩ˞˧ጯ็ጱĂЯѩдᕖૺّ
͕҉ঽត ( dilated cardiomyopathy ) ϐഇ۞ঽˠĂ
ࣇ۞҉̈ሇ ( trabeculae ) ጐგ̪ᖞᏲчڱᜋҹ Ϋ྿ڒؠޠĂҭߏдТᇹܜޘ̝˭ࣇ࠹ᑕயϠ
۞˧ณݒഴ͌ధк54Ą
ܜ˳۞͕҉۲̂ޢΞਕົតјᕖૺّ͕҉
ঽតĂѩॡ̙ҭ͕ވ҉҇តᓠă۩ม˵ត̂Ą
࣎ត̼Ξਕҡᐌ͕҉ࡪ۞ࣟ˸51Ăֹ౺ዶ
͕҉۞ఈՀࠎΐࢦĂЯѩซˢೋّೈᒖăΐి
͕҉ࡪ۞ࣟ˸Ăޢጱᚑࢦ۞͕აĄϫ
݈ѣࡁտֱૺ˧͔۞͕҉ࡪࣟ˸Ξਕ ᄃࡪ፬৵۞צጡѣᙯ55Ą
ᓜԖᑕϡ
ঽநّ͕҉۲ݓ̪ጱ͕აĄϫ
݈၆ٺ͕აଈ۰˘ฟؕ۞෧ᕝ఼૱ౌߏͽᓜ Ԗ۞াېࠎጱШĂГ੨Ъၹౄ়ّ͕ঽ۞ѣ
ᄃᚑࢦޘĄᓜԖাې̶ഇ૱ֹϡ۞ณܑߏ৸ ࡗ͕םົ ( NYHA ) ֶፂাېᚑࢦޘٙઇ۞
α࣎Αਕ̶ഇćඕၹ়ّ͕ঽ۞ѣߏ࿅
͕ࢰگ៍၅ν͕ވडҕณ ( LVEF )ăν͕ވ
̂̈ăݓޘᄃᘝቯΑਕඈඈֽՙؠ5 6Ą 2001 ѐ
઼়࡚͕ঽጯੰᄃ઼࡚͕םົ ( ACC/AHA ) ӈֶѩ͕აাې۞൴ण̶ࠎαഇĂ̚ A ഇᄃ B ഇ۞ঽˠߏѣז͕ა۞ПᐍЯ̄
ݒᔘ՟ѣځពাېĂ C ഇߏ̏གྷѣ͕ა۞া
ېͷѣඕၹّ۞͕ঽតĂ D ഇߏ͕ა ᚑࢦͷڼᒚड़ڍָ̙۞ଈ۰ćڼᒚࣧ˵ֶፂѩ
̶ഇ҃ѣٙमள57Ą
дν͕ވ۲̂Ъ׀ќᒺΑਕ̙։়̝͕ঽ ଈ۰Ăڼᒚ˯఼૱ͽҕგૺ˧৵ᖼೱ Ժט
( angiotensin converting enzyme inhibitor, ACEI )ă
˙ݭඪ˯ཛྷ৵ܡᕝጡ ( ɘ-blocker ) ᄃӀԌࠎ
Ą̚ҕგૺ˧৵ᖼೱ Ժט58, 59ᄃ˙ݭඪ
˯ཛྷ৵ܡᕝጡ60, 61ਕѣड़Լච͕აঽˠ۞
ޢĂӀԌߏд়ঽഇΞͽԼචវ୵࿅к۞
ଐڶ62Ą
҃Ăጐგϫ݈۞ᘽۏڼᒚ၆ٺҕᑅ۞ଠטמ ѣјड़Ăҭߏд̂ݭ۞ᓜԖࡁտ̚ពϯĂᘽۏ ڼᒚ၆ٺ͕֨҉۲̂۞ड़ڍ̙ၓ63ĂࠤҌ̙т γࡊڼᒚֽѣड़64ć҃ͷӈֹд᎕ໂ۞ڼᒚ̝
˭Ăֱ͕აଈ۰۞Ѫ˸தᄃᎮঽதౌا
̙˭58, 59, 61, 62
ĄΩ˘͞ࢬĂధкࡁտϺᓜԖা
ېᄃ၁ᅫ͕Αਕ۞࠹ᙯّઐҲĂাې۞ᚑࢦ
ޘــڱϤν͕ވडҕͧதҲֽͅߍ65Ą дᇹ۞ଐڶ˭ԧࣇᅮࢋՀซ˘ՎăࠤҌߏ Ξͽณ̼۞ᇾֽീ়͕ঽଈ۰۞ޢĄ݈
ৠགྷّෲႬᄋ۞፧ޘߏႾീ͕ఈᄃଯҤ͕
়ঽޢ۞ϲᇾᄫ66-68Ă̚˫ͽ BNP ( প Ҿߏ N-BNP ) ࠎϫ݈੫၆ν͕ވΑਕᄃޢࢦ
ࢋ۞ീЯ̄69-72Ą Troughton ඈˠٺ 2000 ѐ൴
ܑ۞ᓜԖ၁រͽҕ BNP ፧ޘࠎጱШ۞ڼ ᒚĂྵ็۞ᓜԖাېጱШڼᒚਕՀѣड़Լត͕
়ঽଈ۰۞ޢăؼᏵௐ˘Ѩ়ঽ൴ү۞ॡ มć҃᎕ໂ۞ڼᒚϺΞࢫҲ B N P ۞፧ޘ7 3Ąд 2 0 0 5ѐ઼࡚͕ጯੰᄃ઼࡚͕םົࢎ۞ᓜ Ԗ͔ ( ACC/AHA guidelines ) ̏̚གྷ BNP Е ࠎ class IIa ۞෧ᕝᇾĂͷ၁ᙋૄᖂࠎ A ৺ćͅ
៍૱ϡ۞ᓜԖাې̶৺Ă၁ᙋૄᖂݒкΪѣ C
৺56ĂΞ֍ BNP ጱШ۞෧ᕝڼᒚᗓᓜԖ˯۞ᇃ ھᑕϡᔘѣ࠹༊̂۞ซՎ۩มĄ
ඕᄬᄃϏֽण୕
זϫ݈ࠎͤ۞ࡁտౌĂ͕ૺ˧۞Լតົ
͔൴˘ాҚ࠹༊ᘀᗔ۞ੈཱི็ᅍĂᖎ̼ࠤҌಏ˘۞
ੈཱི็ᅍրҬͼ̙֭хдĄிк۞ੈཱི็ᅍր
̝ม˫ѣ࠹༊ღ۞ᓑЪĂ҃ԧࣇ၆ٺ࣎ր̪
Ϗѣ఼ሹᒢྋĄѣˠᄮࠎϠநّ۲̂ᄃঽநّ۲̂
ߏࠧቢ̙ځ۞Ѝᙉć˵ѣˠᄮࠎֱ˧ጯ็ጱ۞ੈ
ཱིώ֗ಶΞ̶јዋᑕᄃεአ7 4 , 7 5
Ăညߏ c a l - c i n e u r i nᄃ R a s ۞߿ّಶপҾᄃঽநّ۲̂࠹
ᙯ76ć˘ਕۺؠ۞ߏĂ͔ېڶ۞ྮश ѣ࠹༊۞ࢦᝑ77ĄϤٺ࣎ր۞ኑᗔّҌ̫
إϏਕځᒢĂЯѩ࣐ࡶۡତܡᕝੈཱི็ᅍ࿅
̚۞˘ᒖĂΞਕົ͔൴ᙱͽफ़۞ޢڍĄԆБ
ͻ calcineurin ۞̈ဂĂࣇ۞่͕̙ྵϒ૱ࠎ
̈Ăдࢬ၆࿅ᑅ˧ఈॡ˵ڱயϠϒ૱۞۲
̂ͅᑕ78Ă҃Ժט calcineurin ˵ົܡᘣྻજ͔ٙ
۞Ϡநّ͕۲̂யϠ79ćՀѣˠᄮࠎֱ͕
۲̂ੈཱི็ጱ۞ྮशυืࢋჯૄώ۞߿ّ̖
Ξͽ͕֨ͤࡪᒺ80Ą
ྵࠎΞҖ۞͞ёߏԺטੈཱིజྋቅ̝ޢ۞
а㒝ଠטĂ̚˘ּ࣎̄ߏາ۞ԩҕᑅᘽۏ vasopeptidaseԺט ( VPIs )81Ăι̙ҭΞͽԺט ACE۞үϡĂ˵Ξͽ֨ͤ neutral endopeptidase
̶ྋ natriuretic peptide82ă adrenomedullin ᄃ bradykininĄ Omapatrilat ߏᓜԖ˯Ξϡ۞ VPI Ă дˠᙷ۞ࡁտ̚൴னιΞͽѣड़ࢫҲќᒺᑅᄃන
ૺᑅ81Ă҃ͷдᗕ۠۞ᐌ፟ᓜԖ၁រ̚ĂՀពϯ omapatrilatྵ lisinopril ਕՀࠎѣड़۞ڼᒚ͕
აঽˠ83Ąϫ݈ᙯٺ͞ࢬ۞ࡁտ̪ѣధкإϏ ᗃ۞ొ̶Ă࠹ܫϏֽд̙გᘽۏࡁ൴ٕᓜ Ԗᑕϡ˯ౌѣ࠹༊۞ሕ˧Ą
ણ҂͛ᚥ
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Cardiac Mechanotransduction in Left Ventricular Hypertrophy
Yao-Sheng Yuan, and Chuen-Den Tseng
While the heart functions as a pump which pushes the blood through our circulation, the cardiomyocytes not only supply the major force of the pump, but also respond actively to various environmental signals to lower the mechanical loads or adapt themselves to the environmental requirements. It is known that neurohumoral fac- tors and mechanical loads play important roles in the cardiac remodeling process, with the later having extremely great impact on cardiac hypertrophy. Since pathologic hypertrophy is an independent risk factor of many heart diseases, understanding how mechanical loads contribute to cardiac hypertrophy is necessary for cardiologists.
Cardiac mechanotransduction indicates the process in which the cardiomyocytes sense the change of mechan- ical loads and react. It can be compared to the coding and decoding process of sending orders to the computer.
When the loading of heart increases (new orders), the signals must be detected and coded by proper molecules (the keyboard), then transferred by second messengers (digital signals) to the downstream molecules (CPU) thus enables the cell to give proper reactions (decoding and performing orders), such as increasing of contractility, changing of the ion homeostasis, exocytosis and gene expression, etc. The aim of this article is to discuss the pathways involved in cardiac mechanotransduction and their clinical implications. ( J Intern Med Taiwan 2008;
19: 187-196 )
Department of Internal Medicine, National Taiwan University Hospital
