Normal Myocardial Function and Energetics in Volume-Overload Hypertrophy in the Cat

Cooper, George; Puga, Francisco J.; Zujko, Karen J.; Harrison, Carlos E.; Coleman, Henry Neal

doi:10.1161/01.res.32.2.140

Cited by 90 publications

(27 citation statements)

References 30 publications

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“…Volume overload hypertrophy of the feline RV was created as before (20) by creating an atrial septal defect (ASD) via the BlalockHanlon procedure (21). The normally loaded left ventricle (LV) served as a same-animal control in all cases.…”

Section: Methodsmentioning

confidence: 99%

Site-specific Microtubule-associated Protein 4 Dephosphorylation Causes Microtubule Network Densification in Pressure Overload Cardiac Hypertrophy

Panneerselvam

Samanna

Cheng

et al. 2010

Journal of Biological Chemistry

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In severe pressure overload-induced cardiac hypertrophy, a dense, stabilized microtubule network forms that interferes with cardiocyte contraction and microtubule-based transport. This is associated with persistent transcriptional up-regulation of cardiac ␣-and ␤-tubulin and microtubule-stabilizing microtubule-associated protein 4 (MAP4). There is also extensive microtubule decoration by MAP4, suggesting greater MAP4 affinity for microtubules. Because the major determinant of this affinity is site-specific MAP4 dephosphorylation, we characterized this in hypertrophied myocardium and then assessed the functional significance of each dephosphorylation site found by mimicking it in normal cardiocytes. We first isolated MAP4 from normal and pressure overload-hypertrophied feline myocardium; volume-overloaded myocardium, which has an equal degree and duration of hypertrophy but normal functional and cytoskeletal properties, served as a control for any nonspecific growth-related effects. After cloning cDNA-encoding feline MAP4 and obtaining its deduced amino acid sequence, we characterized by mass spectrometry any site-specific MAP4 dephosphorylation. Solely in pressure overload-hypertrophied myocardium, we identified striking MAP4 dephosphorylation at Ser-472 in the MAP4 N-terminal projection domain and at Ser-924 and Ser-1056 in the assembly-promoting region of the C-terminal microtubule-binding domain. Site-directed mutagenesis of MAP4 cDNA was then used to switch each serine to non-phosphorylatable alanine. Wild-type and mutated cDNAs were used to construct adenoviruses; microtubule network density, stability, and MAP4 decoration were assessed in normal cardiocytes following an equivalent level of MAP4 expression. The Ser-924 3 Ala MAP4 mutant produced a microtubule phenotype indistinguishable from that seen in pressure overload hypertrophy, such that Ser-924 MAP4 dephosphorylation during pressure overload hypertrophy may be central to this cytoskeletal abnormality.Although many important alterations have been described in the properties of hypertrophied myocardium, the mechanisms responsible for contractile dysfunction and many other maladaptive changes of cardiac muscle cells, or cardiocytes, have yet to be fully defined. Although most research in this area has focused on structural and regulatory changes within the myofilament, it has also been found that changes in the microtubule component of the extra-myofilament cytoskeleton may lead both to contractile dysfunction by increasing the internal resistance to sarcomere motion (1, 2) and to disordered cellular homeostasis by impeding cytoskeleton-based intracellular transport (3-6).Our major original finding was that, in severe pressure overload cardiac hypertrophy with increased ventricular wall stress, there is the early appearance and then the persistence of a dense microtubule network and associated contractile dysfunction (7,8). We have now found several synergistic bases for this dense microtubule network. First, during hypertrophy there is persistent tran...

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Section: Methodsmentioning

confidence: 99%

Site-specific Microtubule-associated Protein 4 Dephosphorylation Causes Microtubule Network Densification in Pressure Overload Cardiac Hypertrophy

Panneerselvam

Samanna

Cheng

et al. 2010

Journal of Biological Chemistry

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“…In direct contrast to data for dogs subjected to aortic stenosis, colchicine caused a clear decrease in LV contractility (1-2 and 4) it must then be found in that infected animal. Thus, in the initial study of cardiocytes from the pressure-overloaded feline RV (29), controls consisted of nonhypertrophied cardiocytes from the normally loaded LV from the same animal and equivalently hypertrophied cardiocytes from the volume-overloaded feline RV, which was known to exhibit normal contractile function (5). In neither control were the linked cytoskeletal and contractile defects present.…”

Section: Is There a Specific Link Between Microtubule Network Densitymentioning

confidence: 99%

Cytoskeletal networks and the regulation of cardiac contractility: microtubules, hypertrophy, and cardiac dysfunction

Cooper

2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…Thus, the depression of contractile state observed in these studies may have resulted from examination of muscles before sufficient time had elapsed for complete recovery of function. Also, it has been clearly demonstrated that contractile state of myocardium hypertrophied by volume loading is normal (11,12), further suggesting that contractile state is more closely related to the conditions producing hypertrophy than to the increase in muscle mass per se.…”

Section: Introductionmentioning

confidence: 99%

Normal Contractile State of Hypertrophied Myocardium after Pulmonary Artery Constriction in the Cat

Williams¹,

Potter²

1974

J. Clin. Invest.

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A B S T R A C T The contractile function of right ventricular papillary muscles from normal cats and cats in which the pulmonary artery had been constricted for 6 or 24 wk was examined. Acute pulmonary artery constriction reduced cross-sectional area by an average of 70%, resulting in a 30% mortality from congestive heart failure, all such deaths occurring within the first 3 wk after banding. The increase in right ventricular mass in animals surviving for 6 or 24 wk was similar, averaging 70%. No banded animals had evidence of congestive heart failure at the time of sacrifice, and cardiac output and right atrial pressures were similar to those in control animals.6 wk after banding, the active length-tension curve, maximal rate of rise of isometric force, force-velocity relations, and isometric force with paired stimulation and norepinephrine were all significantly depressed when compared to their respective values in control animals. In contrast, none of these variables was significantly different from control values in animals banded for 24 wk. These observations indicate that depressed contractile state is not a fundamental characteristic of pressureinduced hypertrophied myocardium and reemphasize the important temporal relationship between contractile state and the imposition of sudden sustained loads.

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Normal Myocardial Function and Energetics in Volume-Overload Hypertrophy in the Cat

Cited by 90 publications

References 30 publications

Site-specific Microtubule-associated Protein 4 Dephosphorylation Causes Microtubule Network Densification in Pressure Overload Cardiac Hypertrophy

Site-specific Microtubule-associated Protein 4 Dephosphorylation Causes Microtubule Network Densification in Pressure Overload Cardiac Hypertrophy

Cytoskeletal networks and the regulation of cardiac contractility: microtubules, hypertrophy, and cardiac dysfunction

Normal Contractile State of Hypertrophied Myocardium after Pulmonary Artery Constriction in the Cat

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