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Lipopolysaccharide Activates Calcineurin in Ventricular Myocytes

Jun Suzuki, MD, PhD^_*,,_*, Evelyn Bayna, PhD^_*, Hai Ling Li, PhD^_*, Erminia Dalle Molle, BS^_*, and Wilbur Y.W. Lew, MD, FACC^_*,

^_* Cardiology Section, Department of Medicine, V.A. San Diego Healthcare System, San Diego, California
University of California, San Diego, San Diego, California

Manuscript received November 1, 2005; revised manuscript received August 31, 2006, accepted September 1, 2006.

^_* Reprint requests and correspondence: Dr. Wilbur Y. W. Lew, Cardiology Section 111A, V. A. San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, California 92161. (Email: wlew{at}ucsd.edu).

OBJECTIVES: We investigated whether lipopolysaccharide (LPS), a proximate cause of inflammation, activates calcineurin in cardiac myocytes and if calcineurin regulates apoptosis in this setting.

BACKGROUND: Calcineurin regulates myocardial growth and hypertrophy, but its role in inflammation is unknown. Calcineurin has proapoptotic or antiapoptotic effects depending on the stimuli.

METHODS: Calcineurin activity was measured in left ventricular myocytes from adult Sprague Dawley rats. Cardiac apoptosis was measured by terminal deoxy-nucleotidyl transferase-mediated dUTP nick end-labeling staining and caspase-3 activity after in vitro and in vivo exposure to LPS.

RESULTS: Lipopolysaccharide increased calcineurin activity in myocytes over 1 to 24 h (t 1/2 = 4.8 h) with an EC₅₀ of 0.80 ng/ml LPS (p < 0.05, n = 4). The LPS (10 ng/ml) effects were mimicked by angiotensin II (Ang II) (100 nmol/l); both increased calcineurin activity and induced apoptosis without additive effects (p < 0.05, n = 5 to 9). Lipopolysaccharide and/or Ang II effects were prevented by 1 h pre-treatment with an Ang II type 1 receptor blocker (losartan, 1 µmol/l), calcineurin inhibitor (cyclosporin A, 0.5 µmol/l), calcium chelator (1,2-Bis(2-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl) ester, 0.1 µmol/l), or by inhibiting sarcoplasmic reticulum (SR) calcium (Ca)-ATPase (thapsigargin, 1 µmol/l) or SR calcium release channel (ryanodine, 1 µmol/l). Left ventricular apoptosis increased from 4 to 24 h after LPS (1 mg/kg intravenously) in vivo, but not in rats pre-treated with cyclosporin A (20 mg/kg/day subcutaneously) for 3 days (p < 0.05, n = 5).

CONCLUSIONS: In cardiac myocytes, LPS activates calcineurin in association with apoptosis by Ang II and SR calcium-dependent mechanisms. This expands the paradigm for cardiac calcineurin to be activated by low levels of LPS in inflammation and chronic conditions (e.g., infections, smoking, and heart failure).

Abbreviations and Acronyms   Ang II = angiotensin II   AT1 = angiotensin II type 1 receptor   BAPTA-AM = 1,2-Bis(2-amino-5-fluorophenoxy)ethane- N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl) ester   LPS = lipopolysaccharide   MPT = mitochondrial permeability transition pore   RyR = ryanodine receptor   SR = sarcoplasmic reticulum   TLR-4 = Toll-like receptor-4   TUNEL = terminal deoxy-nucleotidyl transferase-mediated dUTP nick end-labeling

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