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Reversal of Calcium Cycling Defects in Advanced Heart Failure

Toward Molecular Therapy

Masahiko Hoshijima, MD, PhD^_*,, Ralph Knöll, MD, PhD^_*, Mohammad Pashmforoush, MD, PhD^_* and Kenneth R. Chien, MD, PhD^_*,,_*

^_* Institute of Molecular Medicine, University of California San Diego, La Jolla, California
Center for Research in Biological Systems, University of California San Diego, La Jolla, California
Cardiovascular Research Center, Massachusetts General Hospital, Department of Cell Biology, Harvard Medical School, the Harvard Stem Cell Institute, Boston, Massachusetts.

View larger version (50K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Muscle-specific LIM protein (MLP)-deficient (MLPKO) mice share a broad spectrum of pathological phenotypes with human dilated cardiomyopathy (DCM). Note defective Z disc found in the MLP-null myocardium. APD = action potential duration; SR = sarcoplasmic reticulum; ßAR = beta-adrenergic receptor.

View larger version (74K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Z disc-related mechanical sensor cross-talks with receptor-dependent signaling. Transmembrane receptors including gp130 cytokine receptors, erbB2-erbB4, and insulin-like growth factor-1 receptor (IGF1-R) activate multiple signal kinase cascades that regulate cell protective gene programs. A calcium-activated calcineurin dephosphorylates multiple cellular substrates including transcriptional regulators that regulate cardiac remodeling. Cardiomyocytes, on the other hand, have (perhaps multiple) mechanical stress sensors inside of the cells, and the titin-T-cap-muscle-specific LIM protein (MLP) complex constitutes such a sensor systems associated with Z discs (24). Akt = protein kinase B; Jak = Janus kinase; MAP = mean arterial pressure; MKK = mitogen-activated protein kinase kinase; PDK1 = phosphoinositide-dependent protein kinase 1; SR = sarcoplasmic reticulum; Stat3 = signal transducer and activator of transcription-3.

View larger version (54K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Regulatory systems of cardiac excitation-contraction coupling and the gene therapy targeting sarcoplasmic reticulum (SR) calcium uptake. (A) Intracellular mobilization of calcium ions governs myofilament contraction and relaxation. Two calcium release channels, the L-type calcium channel and ryanodine receptor (RyR), and a regulator of SR calcium uptake, phospholamban (PLN), are key controllers of calcium mobilization under the control of 2 second-messenger-regulated kinases, cyclic adenosine monophosphate (AMP)-dependent kinase (PKA) and calcium-calmodulin-dependent kinase II (CaMKII) (42). S16EPLN therapy directly targets SR calcium uptake (see text for details). (B) A working model of PLN-dependent SR calcium ATPase 2 (SERCA2) regulation has been refined, based on recent studies by Mueller et al. (61) and Zamoon et al. (62). Phospholamban is tightly bound to SERCA2 due to their low dissociation constant. Physiologically, high calcium concentration or PLN phosphorylation induces conformational changes of the cytoplasmic domain of PLN, which results in a structural rearrangement of PLN-SERCA2 interaction (from an inactive complex to an active complex) without dissociation. S16EPLN structurally resembles the Ser16-phosphoylated form PLN. Thus, S16EPLN transfection may stably constitute an active SERCA2-S16EPLN complex in cardiomyocytes. ARK = adrenergic receptor kinase; ßAR = beta-adrenergic receptor; FKBP = K506 binding protein; NCX = Na-Ca exchanger.

View larger version (88K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Chronic therapeutic effects of S16EPLN/rAAV-treatment in post-myocardial infarction (MI) rats. Serial changes of echocardiographic variables (A to C) before and after S16EPLN gene transfer and pulse-wave Doppler imaging of mitral flow found in sham (no-MI) rats (D), saline-treated post-MI rats (E), and S16EPLN-treated post-MI rats (F). Note elevated early filling velocity and diminished late filling found in saline-treated post-MI rats were normalized in S16EPLN-treated animals. Suppression of the induction of interstitial fibrosis in the non-infarcted region in S16EPLN-treated animals was obvious (G to I). (G) Sham (no-MI) rat myocardium; (H) Saline-treated post-MI rat myocardium; (I) S16EPLN-treated post-MI rat myocardium. Modified from figures in Iwanaga et al. (56). LVEDV = left ventricular end-diastolic volume; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume.