Myofilament Ca2+ desensitization mediates positive lusitropic effect of neuronal nitric oxide synthase in left ventricular myocytes from murine hypertensive heart

Chun Zi Jin, Ji Hyun Jang, Hae Jin Kim, Yue Wang, In Chang Hwang, Sakthivel Sadayappan, Byung Mun Park, Suhn Hee Kim, Zhe Hu Jin, Eun Yeong Seo, Kyung Hee Kim, Yong Jin Kim, Sung Joon Kim, Yin Hua Zhang

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Neuronal nitric oxide synthase (NOS1 or nNOS) exerts negative inotropic and positive lusitropic effects through Ca2+ 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 [Ca2+]i transient was increased in HP. Concomitantly, relaxation and time constant of [Ca2+]i decay (tau) were faster and the phosphorylated fraction of phospholamban (PLN-Ser16/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 [Ca2+]i transient; prevented faster relaxation without affecting the tau of [Ca2+]i transient or PLN-Ser16/PLN in HP, suggesting myofilament Ca2+ desensitization by NOS1. Indeed, relaxation phase of the sarcomere length-[Ca2+]i relationship of LV myocytes shifted to the right and increased [Ca2+]i for 50% of sarcomere shortening (EC50) in HP. Phosphorylations of cardiac myosin binding protein-C (cMyBP-C282 and cMyBP-C273) were increased and cardiac troponin I (cTnI23/24) was reduced in HP. Importantly, NOS1 or PKG inhibition reduced cMyBP-C273 and cTnI23/24 and reversed myofilament Ca2+ sensitivity. These results reveal that NOS1 is up-regulated in LV myocytes from HP and exerts positive lusitropic effect by modulating myofilament Ca2+ sensitivity through phosphorylation of key regulators in sarcomere.

Original languageEnglish
Pages (from-to)107-115
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume60
Issue number1
DOIs
StatePublished - Jul 2013

Keywords

  • Cardiac myosin binding protein-C
  • Cardiac troponin I
  • Hypertension
  • Left ventricular myocyte
  • Myofilament Ca sensitivity
  • NOS1
  • Relaxation

Cite this