title: Myofilament Ca2+ desensitization mediates positive lusitropic effect of neuronal nitric oxide synthase in left ventricular myocytes from murine hypertensive heart.
abstract: Neuronal nitric oxide synthase (NOS1 or nNOS) exerts negative inotropic and positive lusitropic effects through Ca(2+) handling processes in cardiac myocytes from healthy hearts. However, underlying mechanisms of NOS1 in diseased hearts remain unclear. The present study aims to investigate this question in angiotensin II (Ang II)-induced hypertensive rat hearts (HP). Our results showed that the systolic function of left ventricle (LV) was reduced and diastolic function was unaltered (echocardiographic assessment) in HP compared to those in shams. In isolated LV myocytes, contraction was unchanged but peak [Ca(2+)]i transient was increased in HP. Concomitantly, relaxation and time constant of [Ca(2+)]i decay (tau) were faster and the phosphorylated fraction of phospholamban (PLN-Ser(16)/PLN) was greater. NOS1 protein expression and activity were increased in LV myocyte homogenates from HP. Surprisingly, inhibition of NOS1 did not affect contraction but reduced peak [Ca(2+)]i transient; prevented faster relaxation without affecting the tau of [Ca(2+)]i transient or PLN-Ser(16)/PLN in HP, suggesting myofilament Ca(2+) desensitization by NOS1. Indeed, relaxation phase of the sarcomere length-[Ca(2+)]i relationship of LV myocytes shifted to the right and increased [Ca(2+)]i for 50% of sarcomere shortening (EC50) in HP. Phosphorylations of cardiac myosin binding protein-C (cMyBP-C(282) and cMyBP-C(273)) were increased and cardiac troponin I (cTnI(23/24)) was reduced in HP. Importantly, NOS1 or PKG inhibition reduced cMyBP-C(273) and cTnI(23/24) and reversed myofilament Ca(2+) sensitivity. These results reveal that NOS1 is up-regulated in LV myocytes from HP and exerts positive lusitropic effect by modulating myofilament Ca(2+) sensitivity through phosphorylation of key regulators in sarcomere.
authors.affiliation: Department of Physiology, Ischemic/Hypoxic Disease Institute, Seoul National University, College of Medicine, Seoul, Republic of Korea.
authors.forename: Chun Zi
authors.initials: CZ
authors.lastname: Jin
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Jang
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: In-Chang
authors.initials: IC
authors.lastname: Hwang
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Sadayappan
authors.forename: Byung Mun
authors.initials: BM
authors.lastname: Park
authors.forename: Suhn Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Zhe Hu
authors.initials: ZH
authors.lastname: Jin
authors.forename: Eun Yeong
authors.initials: EY
authors.lastname: Seo
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Kim
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Kim
authors.forename: Sung Joon
authors.initials: SJ
authors.lastname: Kim
authors.forename: Yin Hua
authors.initials: YH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D006351:Heart Valves / Q000201:enzymology / Q000473:pathology; D006973:Hypertension / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009210:Myofibrils / Q000201:enzymology* / Q000473:pathology; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D002118:Calcium