Matrix remodeling in experimental and human heart failure:  a possible regulatory role for TIMP-3

In the failing heart, an imbalance in matrix metalloproteinases (MMPs) and their biological regulators, the tissue inhibitors of MMPs (TIMPs), may result in cardiac dilatation from matrix degradation. We hypothesized that a reduction of myocardial TIMP-3 is associated with adverse matrix remodeling in both human and experimental heart failure. Cardiomyopathic hamsters at age 15 wk (normal), 25 wk (compensated stage), and 35 wk (overt failure) were compared with age-matched normal controls. MMP activity (gelatinase bioassay) was increased in cardiomyopathic hearts ( P = 0.03) and peaked during the transition to overt heart failure. TIMP-3 content (immunoblot) was decreased compared with normal controls (74 ± 5% at 25 wk, 69 ± 10% at 35 wk; P = 0.001) and its reduction was associated with increased MMP activity ( r = −0.6; P = 0.004). TIMP-1 increased progressively ( P = 0.001), whereas TIMP-2, TIMP-4, and MMP protein levels were unchanged. Myocardial collagen (hydroxyproline content) increased with time during the progression to end-stage cardiac failure ( P < 0.0001). Collagen synthesis ([14C]proline uptake) was elevated in cardiomyopathy at 15 and 25 wk ( P < 0.05). The collagen cross-linking ratio (insoluble:soluble collagen) was reduced ( P = 0.003) as the left ventricle dilated. By confocal microscopy restricted to viable myocardium, collagen content was reduced ( P = 0.04) with fragmentation ( P < 0.0001) and thinning ( P = 0.003) of perimysial collagen fibers. Similarly, patients with end-stage congestive heart failure ( n = 7) compared with nonfailing controls ( n = 2) had elevated gelatinase MMP activity ( P = 0.02) associated with isolated reductions in TIMP-3 (55 ± 5% of normal; P = 0.003). Reductions of TIMP-3 parallel adverse matrix remodeling in the cardiomyopathic hamster and the failing human heart. TIMP-3 may contribute to the regulation of myocardial remodeling and its reduction may promote a transition from compensated to end-stage congestive heart failure.

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Human heart failure: cAMP stimulation of SR Ca2+-ATPase activity and phosphorylation level of phospholamban

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.277.2.h474 ◽

1999 ◽

Vol 277 (2) ◽

pp. H474-H480 ◽

Cited By ~ 12

Author(s):

Ulrich Schmidt ◽

Roger J. Hajjar ◽

Catherine S. Kim ◽

Djamel Lebeche ◽

Angelia A. Doye ◽

...

Keyword(s):

Heart Failure ◽

Atpase Activity ◽

Human Heart ◽

Human Myocardium ◽

Human Heart Failure ◽

Protein Levels ◽

Phosphorylation Level ◽

End Stage Heart Failure ◽

End Stage ◽

Camp Stimulation

Failing human myocardium has been associated with decreased sarcoplasmic reticulum (SR) Ca2+-ATPase activity. There remains controversy as to whether the regulation of SR Ca2+-ATPase activity is altered in heart failure or whether decreased SR Ca2+-ATPase activity is due to changes in SR Ca2+-ATPase or phospholamban expression. We therefore investigated whether alterations in cAMP-dependent phosphorylation of phospholamban may be responsible for the reduced SR Ca2+-ATPase activity in human heart failure. Protein levels of phospholamban and SR Ca2+-ATPase, detected by Western blot, were unchanged in failing compared with nonfailing human myocardium. There was decreased responsiveness to the direct activation of the SR Ca2+-ATPase activity by either cAMP (0.01–100 μmol/l) or protein kinase A (1–30 μg) in failing myocardium. Using the backphosphorylation technique, we observed a decrease of the cAMP-dependent phosphorylation level of phospholamban by 20 ± 2%. It is concluded that the impaired SR function in human end-stage heart failure may be due, in part, to a reduced cAMP-dependent phosphorylation of phospholamban.

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ISCHEMIC VERSUS NON-ISCHEMIC RIGHT VENTRICULAR TRANSCRIPTOME IN END-STAGE HUMAN HEART FAILURE

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(14)60921-9 ◽

2014 ◽

Vol 63 (12) ◽

pp. A921

Author(s):

Thomas Gerard Di Salvo ◽

Cristi Galindo ◽

Yan Guo ◽

Yan Ru Su ◽

Tarek bsi ◽

...

Keyword(s):

Heart Failure ◽

Right Ventricular ◽

Human Heart ◽

Human Heart Failure ◽

End Stage

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Abstract 100: Integrated Cardiac Metabolism In End-Stage Human Heart Failure

Circulation Research ◽

10.1161/res.129.suppl_1.100 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Emily Flam ◽

Cholsoon Jang ◽

Ken Bedi ◽

Danielle Murashige ◽

Yifan Yang ◽

...

Keyword(s):

Heart Failure ◽

Human Heart ◽

Glycogen Synthesis ◽

Cardiac Metabolism ◽

Pentose Phosphate ◽

Metabolic Changes ◽

Phospholipid Content ◽

Human Heart Failure ◽

Nucleotide Synthesis ◽

End Stage

Heart failure affects millions of people worldwide with mortality near 50% within five years. This disease is characterized by widespread cardiac and systemic metabolic changes, but a comprehensive evaluation of metabolism in failing human hearts is lacking. Here, we provide a comprehensive depiction of cardiac and systemic metabolic changes in 89 explanted failing and non-failing human hearts through integration of plasma and cardiac tissue metabolomics, genome-wide RNAseq, and proteomic data. The data confirm a profound bioenergetic defect in end-stage human heart failure and demonstrate extensive changes in metabolic homeostasis. The data indicate a substantial defect in fatty acid (FA) use in failing hearts, in particular unsaturated FAs. Reduction of FAs and acyl-carnitines in failing tissue in contrast to concomitant elevations in plasma suggest a defect in import of FAs into the cell, rather than a defect in FA oxidation. Intermediates of glycolysis, the pentose phosphate pathway, and glycogen synthesis are all similarly reduced, as is expression of GLUT1, indicating diminished glucose uptake. However, there was no significant change in tissue pyruvate content, suggesting an increase in lactate utilization. The data suggest increased flux of pyruvate into mitochondria, likely promoting pyruvate oxidation but not pyruvate carboxylation. Blunted anabolic pyruvate flux, in turn, likely leads to insufficient TCA cycle intermediates. Ketone levels were increased in both failing tissue and plasma, as previously reported. The phospholipid content of failing human hearts is greatly increased in both failing tissue and plasma. Nucleotide synthesis pathways also appear to be reprogrammed, with a notable decrease in adenosine metabolism, specifically. Together, these data indicate widespread change in the local cardiac and greater systemic metabolic landscape in severe human heart failure.

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Intracellular Dyssynchrony of Diastolic Cytosolic [Ca 2+ ] Decay in Ventricular Cardiomyocytes in Cardiac Remodeling and Human Heart Failure

Circulation Research ◽

10.1161/circresaha.113.300895 ◽

2013 ◽

Vol 113 (5) ◽

pp. 527-538 ◽

Cited By ~ 39

Author(s):

Felix Hohendanner ◽

Senka Ljubojević ◽

Niall MacQuaide ◽

Michael Sacherer ◽

Simon Sedej ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Remodeling ◽

Human Heart ◽

Cyclopiazonic Acid ◽

Cardiomyocyte Hypertrophy ◽

Human Heart Failure ◽

Mitochondrial Density ◽

Human Cardiomyocytes ◽

End Stage ◽

The Impact

Rationale : Synchronized release of Ca 2+ into the cytosol during each cardiac cycle determines cardiomyocyte contraction. Objective: We investigated synchrony of cytosolic [Ca 2+ ] decay during diastole and the impact of cardiac remodeling. Methods and Results: Local cytosolic [Ca 2+ ] transients (1-µm intervals) were recorded in murine, porcine, and human ventricular single cardiomyocytes. We identified intracellular regions of slow (slowCaR) and fast (fastCaR) [Ca 2+ ] decay based on the local time constants of decay (TAU local ). The SD of TAU local as a measure of dyssynchrony was not related to the amplitude or the timing of local Ca 2+ release. Stimulation of sarcoplasmic reticulum Ca 2+ ATPase with forskolin or istaroxime accelerated and its inhibition with cyclopiazonic acid slowed TAU local significantly more in slowCaR, thus altering the relationship between SD of TAU local and global [Ca 2+ ] decay (TAU global ). Na + /Ca 2+ exchanger inhibitor SEA0400 prolonged TAU local similarly in slowCaR and fastCaR. FastCaR were associated with increased mitochondrial density and were more sensitive to the mitochondrial Ca 2+ uniporter blocker Ru360. Variation in TAU local was higher in pig and human cardiomyocytes and higher with increased stimulation frequency (2 Hz). TAU local correlated with local sarcomere relengthening. In mice with myocardial hypertrophy after transverse aortic constriction, in pigs with chronic myocardial ischemia, and in end-stage human heart failure, variation in TAU local was increased and related to cardiomyocyte hypertrophy and increased mitochondrial density. Conclusions: In cardiomyocytes, cytosolic [Ca 2+ ] decay is regulated locally and related to local sarcomere relengthening. Dyssynchronous intracellular [Ca 2+ ] decay in cardiac remodeling and end-stage heart failure suggests a novel mechanism of cellular contractile dysfunction.

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