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result sql = Alterations of phospholamban function can exhibit cardiotoxic effects independent of excessive sarcoplasmic reticulum Ca2+-ATPase inhibition.

Alterations of phospholamban function can exhibit cardiotoxic effects independent of excessive sarcoplasmic reticulum Ca2+-ATPase inhibition.

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char = e;code = 101
char = l;code = 108
char = y;code = 121
char = );code = 41
char = .;code = 46
char = ;code = 32
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = -;code = 45
char = /;code = 47
char = -;code = 45
char = );code = 41
char = ;code = 32
char = +;code = 43
char = T;code = 84
char = g;code = 103
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = R;code = 82
char = 9;code = 57
char = C;code = 67
char = );code = 41
char = ;code = 32
char = h;code = 104
char = e;code = 101
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = s;code = 115
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char = d;code = 100
char = e;code = 101
char = m;code = 109
char = o;code = 111
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char = s;code = 115
char = t;code = 116
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = a;code = 97
char = c;code = 99
char = c;code = 99
char = e;code = 101
char = l;code = 108
char = e;code = 101
char = r;code = 114
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = s;code = 115
char = a;code = 97
char = r;code = 114
char = c;code = 99
char = o;code = 111
char = p;code = 112
char = l;code = 108
char = a;code = 97
char = s;code = 115
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = u;code = 117
char = l;code = 108
char = u;code = 117
char = m;code = 109
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char = C;code = 67
char = a;code = 97
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char = 2;code = 50
char = +;code = 43
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char = ;code = 32
char = u;code = 117
char = p;code = 112
char = t;code = 116
char = a;code = 97
char = k;code = 107
char = e;code = 101
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char = r;code = 114
char = a;code = 97
char = t;code = 116
char = e;code = 101
char = s;code = 115
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = i;code = 105
char = m;code = 109
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = v;code = 118
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = h;code = 104
char = e;code = 101
char = m;code = 109
char = o;code = 111
char = d;code = 100
char = y;code = 121
char = n;code = 110
char = a;code = 97
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = s;code = 115
char = ;code = 32
char = c;code = 99
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char = m;code = 109
char = p;code = 112
char = a;code = 97
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = +;code = 43
char = /;code = 47
char = +;code = 43
char = );code = 41
char = +;code = 43
char = T;code = 84
char = g;code = 103
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = R;code = 82
char = 9;code = 57
char = C;code = 67
char = );code = 41
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = b;code = 98
char = u;code = 117
char = t;code = 116
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = l;code = 108
char = l;code = 108
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = s;code = 115
char = p;code = 112
char = o;code = 111
char = n;code = 110
char = d;code = 100
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = p;code = 112
char = o;code = 111
char = o;code = 111
char = r;code = 114
char = l;code = 108
char = y;code = 121
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = t;code = 116
char = a;code = 97
char = -;code = 45
char = a;code = 97
char = d;code = 100
char = r;code = 114
char = e;code = 101
char = n;code = 110
char = e;code = 101
char = r;code = 114
char = g;code = 103
char = i;code = 105
char = c;code = 99
char = ;code = 32
char = s;code = 115
char = t;code = 116
char = i;code = 105
char = m;code = 109
char = u;code = 117
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = b;code = 98
char = e;code = 101
char = c;code = 99
char = a;code = 97
char = u;code = 117
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = R;code = 82
char = 9;code = 57
char = C;code = 67
char = );code = 41
char = ;code = 32
char = i;code = 105
char = m;code = 109
char = p;code = 112
char = a;code = 97
char = i;code = 105
char = r;code = 114
char = s;code = 115
char = ;code = 32
char = p;code = 112
char = r;code = 114
char = o;code = 111
char = t;code = 116
char = e;code = 101
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = a;code = 97
char = s;code = 115
char = e;code = 101
char = ;code = 32
char = A;code = 65
char = -;code = 45
char = m;code = 109
char = e;code = 101
char = d;code = 100
char = i;code = 105
char = a;code = 97
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char = e;code = 101
char = d;code = 100
char = ;code = 32
char = p;code = 112
char = h;code = 104
char = o;code = 111
char = s;code = 115
char = p;code = 112
char = h;code = 104
char = o;code = 111
char = r;code = 114
char = y;code = 121
char = l;code = 108
char = a;code = 97
char = t;code = 116
char = i;code = 105
char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = b;code = 98
char = o;code = 111
char = t;code = 116
char = h;code = 104
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = l;code = 108
char = d;code = 100
char = -;code = 45
char = t;code = 116
char = y;code = 121
char = p;code = 112
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
char = ;code = 32
char = m;code = 109
char = u;code = 117
char = t;code = 116
char = a;code = 97
char = n;code = 110
char = t;code = 116
char = ;code = 32
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = .;code = 46
char = ;code = 32
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = +;code = 43
char = /;code = 47
char = +;code = 43
char = );code = 41
char = +;code = 43
char = T;code = 84
char = g;code = 103
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = R;code = 82
char = 9;code = 57
char = C;code = 67
char = );code = 41
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
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char = d;code = 100
char = i;code = 105
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = h;code = 104
char = e;code = 101
char = a;code = 97
char = r;code = 114
char = t;code = 116
char = ;code = 32
char = f;code = 102
char = a;code = 97
char = i;code = 105
char = l;code = 108
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = ;code = 32
char = a;code = 97
char = t;code = 116
char = ;code = 32
char = 2;code = 50
char = 1;code = 49
char = +;code = 43
char = /;code = 47
char = -;code = 45
char = 6;code = 54
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = w;code = 119
char = h;code = 104
char = e;code = 101
char = r;code = 114
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = ;code = 32
char = h;code = 104
char = e;code = 101
char = t;code = 116
char = e;code = 101
char = r;code = 114
char = o;code = 111
char = z;code = 122
char = y;code = 121
char = g;code = 103
char = o;code = 111
char = u;code = 117
char = s;code = 115
char = ;code = 32
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = +;code = 43
char = /;code = 47
char = -;code = 45
char = );code = 41
char = +;code = 43
char = T;code = 84
char = g;code = 103
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = R;code = 82
char = 9;code = 57
char = C;code = 67
char = );code = 41
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = v;code = 118
char = i;code = 105
char = v;code = 118
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 4;code = 52
char = 8;code = 56
char = +;code = 43
char = /;code = 47
char = -;code = 45
char = 1;code = 49
char = 1;code = 49
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = -;code = 45
char = /;code = 47
char = -;code = 45
char = );code = 41
char = +;code = 43
char = T;code = 84
char = g;code = 103
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = R;code = 82
char = 9;code = 57
char = C;code = 67
char = );code = 41
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 6;code = 54
char = 6;code = 54
char = +;code = 43
char = /;code = 47
char = -;code = 45
char = 1;code = 49
char = 9;code = 57
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = a;code = 97
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char = d;code = 100
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = l;code = 108
char = d;code = 100
char = -;code = 45
char = t;code = 116
char = y;code = 121
char = p;code = 112
char = e;code = 101
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char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
char = ;code = 32
char = t;code = 116
char = o;code = 111
char = ;code = 32
char = 9;code = 57
char = 4;code = 52
char = +;code = 43
char = /;code = 47
char = -;code = 45
char = 2;code = 50
char = 7;code = 55
char = ;code = 32
char = w;code = 119
char = e;code = 101
char = e;code = 101
char = k;code = 107
char = s;code = 115
char = ;code = 32
char = (;code = 40
char = P;code = 80
char = <;code = 60
char = 0;code = 48
char = .;code = 46
char = 0;code = 48
char = 0;code = 48
char = 1;code = 49
char = );code = 41
char = .;code = 46
char = ;code = 32
char = A;code = 65
char = l;code = 108
char = t;code = 116
char = h;code = 104
char = o;code = 111
char = u;code = 117
char = g;code = 103
char = h;code = 104
char = ;code = 32
char = C;code = 67
char = a;code = 97
char = (;code = 40
char = 2;code = 50
char = +;code = 43
char = );code = 41
char = ;code = 32
char = r;code = 114
char = e;code = 101
char = u;code = 117
char = p;code = 112
char = t;code = 116
char = a;code = 97
char = k;code = 107
char = e;code = 101
char = ;code = 32
char = k;code = 107
char = i;code = 105
char = n;code = 110
char = e;code = 101
char = t;code = 116
char = i;code = 105
char = c;code = 99
char = s;code = 115
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = y;code = 121
char = o;code = 111
char = u;code = 117
char = n;code = 110
char = g;code = 103
char = ;code = 32
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = -;code = 45
char = /;code = 47
char = -;code = 45
char = );code = 41
char = +;code = 43
char = T;code = 84
char = g;code = 103
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = R;code = 82
char = 9;code = 57
char = C;code = 67
char = );code = 41
char = ;code = 32
char = m;code = 109
char = i;code = 105
char = c;code = 99
char = e;code = 101
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char = e;code = 101
char = x;code = 120
char = c;code = 99
char = e;code = 101
char = e;code = 101
char = d;code = 100
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = t;code = 116
char = h;code = 104
char = o;code = 111
char = s;code = 115
char = e;code = 101
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char = m;code = 109
char = e;code = 101
char = a;code = 97
char = s;code = 115
char = u;code = 117
char = r;code = 114
char = e;code = 101
char = d;code = 100
char = ;code = 32
char = i;code = 105
char = n;code = 110
char = ;code = 32
char = w;code = 119
char = i;code = 105
char = l;code = 108
char = d;code = 100
char = -;code = 45
char = t;code = 116
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char = p;code = 112
char = e;code = 101
char = ;code = 32
char = c;code = 99
char = o;code = 111
char = n;code = 110
char = t;code = 116
char = r;code = 114
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char = l;code = 108
char = ;code = 32
char = a;code = 97
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char = m;code = 109
char = a;code = 97
char = l;code = 108
char = s;code = 115
char = ,;code = 44
char = ;code = 32
char = t;code = 116
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char = a;code = 97
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char = e;code = 101
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char = a;code = 97
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char = o;code = 111
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char = a;code = 97
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char = s;code = 115
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char = f;code = 102
char = f;code = 102
char = i;code = 105
char = c;code = 99
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char = e;code = 101
char = n;code = 110
char = t;code = 116
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char = t;code = 116
char = o;code = 111
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char = p;code = 112
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char = e;code = 101
char = v;code = 118
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char = n;code = 110
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char = e;code = 101
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char = u;code = 117
char = a;code = 97
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char = e;code = 101
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char = o;code = 111
char = p;code = 112
char = m;code = 109
char = e;code = 101
char = n;code = 110
char = t;code = 116
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char = o;code = 111
char = f;code = 102
char = ;code = 32
char = d;code = 100
char = i;code = 105
char = l;code = 108
char = a;code = 97
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char = e;code = 101
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char = c;code = 99
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char = r;code = 114
char = d;code = 100
char = i;code = 105
char = o;code = 111
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char = y;code = 121
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char = p;code = 112
char = a;code = 97
char = t;code = 116
char = h;code = 104
char = y;code = 121
char = .;code = 46
char = <;code = 60
char = b;code = 98
char = r;code = 114
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char = >;code = 62
char = <;code = 60
char = b;code = 98
char = r;code = 114
char = /;code = 47
char = >;code = 62
char = <;code = 60
char = b;code = 98
char = >;code = 62
char = C;code = 67
char = O;code = 79
char = N;code = 78
char = C;code = 67
char = L;code = 76
char = U;code = 85
char = S;code = 83
char = I;code = 73
char = O;code = 79
char = N;code = 78
char = S;code = 83
char = ;code = 32
char = :;code = 58
char = ;code = 32
char = <;code = 60
char = /;code = 47
char = b;code = 98
char = >;code = 62
char = T;code = 84
char = h;code = 104
char = e;code = 101
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char = d;code = 100
char = a;code = 97
char = t;code = 116
char = a;code = 97
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char = r;code = 114
char = a;code = 97
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char = e;code = 101
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char = a;code = 97
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char = a;code = 97
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char = e;code = 101
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char = h;code = 104
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char = d;code = 100
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char = e;code = 101
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char = i;code = 105
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char = i;code = 105
char = b;code = 98
char = i;code = 105
char = t;code = 116
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char = o;code = 111
char = n;code = 110
char = ;code = 32
char = o;code = 111
char = f;code = 102
char = ;code = 32
char = S;code = 83
char = E;code = 69
char = R;code = 82
char = C;code = 67
char = A;code = 65
char = 2;code = 50
char = a;code = 97
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char = a;code = 97
char = c;code = 99
char = t;code = 116
char = i;code = 105
char = v;code = 118
char = i;code = 105
char = t;code = 116
char = y;code = 121
char = ;code = 32
char = b;code = 98
char = y;code = 121
char = ;code = 32
char = P;code = 80
char = L;code = 76
char = N;code = 78
char = (;code = 40
char = w;code = 119
char = t;code = 116
char = );code = 41
char = ;code = 32
char = a;code = 97
char = n;code = 110
char = d;code = 100
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char = t;code = 116
char = h;code = 104
char = e;code = 101
char = ;code = 32
char = t;code = 116
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result sql = BACKGROUND : Low activity of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) resulting from strong inhibition by phospholamban (PLN) can depress cardiac contractility and lead to dilated cardiomyopathy and heart failure. Here, we investigated whether PLN exhibits cardiotoxic effects via mechanisms other than chronic inhibition of SERCA2a by studying a PLN mutant, PLN(R9C), that triggers cardiac failure in humans and mice.

METHODS AND RESULTS : Because PLN(R9C) inhibits SERCA2a mainly by preventing deactivation of wild-type PLN, SERCA2a activity could be increased stepwise by generating mice that carry a PLN(R9C) transgene and 2, 1, or 0 endogenous PLN alleles (PLN(+/+)+TgPLN(R9C), PLN(+/-)+TgPLN(R9C), and PLN(-/-)+TgPLN(R9C), respectively). PLN(-/-) +TgPLN(R9C) hearts demonstrated accelerated sarcoplasmic reticulum Ca(2+) uptake rates and improved hemodynamics compared with PLN(+/+)+TgPLN(R9C) mice but still responded poorly to beta-adrenergic stimulation because PLN(R9C) impairs protein kinase A-mediated phosphorylation of both wild-type and mutant PLN. PLN(+/+)+TgPLN(R9C) mice died of heart failure at 21+/-6 weeks, whereas heterozygous PLN(+/-)+TgPLN(R9C) mice survived to 48+/-11 weeks, PLN(-/-)+TgPLN(R9C) mice to 66+/-19 weeks, and wild-type mice to 94+/-27 weeks (P<0.001). Although Ca(2+) reuptake kinetics in young PLN(-/-)+TgPLN(R9C) mice exceeded those measured in wild-type control animals, this parameter alone was not sufficient to prevent the eventual development of dilated cardiomyopathy.

CONCLUSIONS : The data demonstrate an association between the dose-dependent inhibition of SERCA2a activity by PLN(wt) and the time of onset of heart failure and show that a weak inhibitor of SERCA2a, PLN(R9C), which is diminished in its ability to modify the level of SERCA2a activity, leads to heart failure despite fast sarcoplasmic reticulum Ca(2+) reuptake.

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