Our studies of the load-specificity of pathological versus physiological hypertrophic cardiac responses to hemodynamic challenges led to the discovery [Science, 260: 682-687, 1993] of a dense cardiocyte microtubule network during pathological, high ventricular wall stress hypertrophy caused by severe pressure-overloading that contributes to the striking contractile and intracellular transport dysfunction that occur in this setting. In attempting to identify the cause for this cytoskeletal abnormality, a crucial hint was provided by the fact that we have never seen microtubule network changes with an equivalent degree and duration of fully compensated physiological hypertrophy wherein ventricular wall stress remains normal. This hint, coupled with the following three further considerations, led to the studies proposed in this application. First, a hallmark of decompensated pathological cardiac hypertrophy is a persistent elevation of circulating and neural catecholamines, such that one would expect this to be present in pathological hypertrophy but absent from compensated physiological hypertrophy. Second, very recent data establish a critical role of b-adrenergic input in increasing the activity of p21-activated kinase, or Pak1, which in turn initiates a cascade of phosphatase activation, specifically of PP2A and then PP1, in the heart. Third, our own data indicate that the abnormal microtubule network seen in pathological cardiac hypertrophy is driven by binding to microtubules of MAP4, the predominant cardiac microtubule-associated structural protein, and that this in turn is driven by phosphatase-dependent site-specific MAP4 dephosphorylation. We propose to use this information here in two specific aims.
In Specific Aim #1, we will attempt to establish the etiological role of b-adrenergic input in causing the hypertrophy- associated cardiac microtubule phenotype by comparing our very well characterized model of feline physiological volume-overload hypertrophy to our equally well characterized model of pathological pressure-overload hypertrophy with or without chronic b-adrenergic blockade. If correct, our hypothesis would predict that the abnormal microtubule network will be present in pressure-overload hypertrophy without b-adrenergic blockade but absent both in this model with b-adrenergic blockade and in the physiological volume-overload model with no drug treatment.
In Specific Aim #2, if we are able in the previous aim to prevent formation of the dense, MAP4-decorated microtubule network by using chronic b-adrenergic blockade in the severe pressure-overload model of which it is characteristic, we will determine whether this also prevents the associated functional abnormalities of contraction and microtubule-based transport.

Public Health Relevance

Congestive heart failure is the leading cause of hospital admission and readmission in Americans aged 65 or greater. The contractile dysfunction and cardiac growth abnormalities that characterize systolic heart failure are a maladaptive myocardial response to several pathological challenges, including sustained cardiac pressure overloading. This study will identify the mechanism underlying one important cause for this dysfunction in the failing heart: alterations in the microtubule network of the cardiac muscle cell cytoskeleton.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Adhikari, Bishow B
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Medical University of South Carolina
Internal Medicine/Medicine
Schools of Medicine
United States
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Cheng, Guangmao; Kasiganesan, Harinath; Baicu, Catalin F et al. (2012) Cytoskeletal role in protection of the failing heart by ?-adrenergic blockade. Am J Physiol Heart Circ Physiol 302:H675-87
Chinnakkannu, Panneerselvam; Samanna, Venkatesababa; Cheng, Guangmao et al. (2010) Site-specific microtubule-associated protein 4 dephosphorylation causes microtubule network densification in pressure overload cardiac hypertrophy. J Biol Chem 285:21837-48
Cheng, Guangmao; Takahashi, Masaru; Shunmugavel, Anandakumar et al. (2010) Basis for MAP4 dephosphorylation-related microtubule network densification in pressure overload cardiac hypertrophy. J Biol Chem 285:38125-40