Protein Kinase G Modulates Human Myocardial Passive Stiffness by Phosphorylation of the Titin Springs

Krüger, Martina; Kötter, Sebastian; Grützner, Anika; Lang, Patrick; Andresen, Christian; Redfield, Margaret M.; Butt, Elke; Remedios, Cris G. dos; Linke, Wolfgang A.

doi:10.1161/circresaha.108.184408

Cited by 358 publications

(293 citation statements)

References 40 publications

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“…This finding could be attributed to decreased phosphorylation of the large elastic cytoskeletal protein titin. Phosphorylation of titin by PKG decreases passive stiffness in cardiac myofibrils, and recent evidence has shown that increased passive stiffness in isolated cardiomyocytes from human HFpEF patients is associated with reduced cGMP levels and subsequent PKG activity 7, 8, 9. Contrary to these findings, cGMP levels and PKG activity were unaltered in the HF group of the current study compared to CON.…”

Section: Discussioncontrasting

confidence: 90%

“…Cyclic guanosine monophosphate (cGMP) levels modulate many signaling pathways regulating diastolic function and may inhibit ventricular hypertrophy and stiffness while promoting diastolic relaxation 5, 6, 7, 8. There is growing evidence the cGMP signaling cascade is disturbed in HFpEF patients and could contribute to diastolic dysfunction 4, 5, 9, 10.…”

Section: Introductionmentioning

confidence: 99%

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Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Hiemstra

Lee

Chakir

et al. 2016

JAHA

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BackgroundCyclic guanosine monophosphate‐protein kinase G‐phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl‐peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function.Methods and ResultsWe assessed LV hypertrophy and function at the organ and cellular level in aortic‐banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end‐systolic pressure‐volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil‐treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening‐frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium‐retention capacity and Complex II‐dependent respiratory control, was present in both HF and tadalafil‐treated animals.ConclusionsBoth saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

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Section: Discussioncontrasting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Hiemstra

Lee

Chakir

et al. 2016

JAHA

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“…Recent evidence indicates that FHL1 functions in the hypertrophic biomechanical stress response (31) and that FHL2 functions in localizing various metabolic enzymes (32). In addition, the N2B-Us contains sequences that can be phosphorylated by PKA (34) and PKG (35) and that thereby tune the compliance of the N2B-Us spring. It is likely that these important N2B-Us functions (binding FHL1/2, responding to phoshorylation) depend on local secondary structures and that ␣B-crystallin is required to maintain these structures, especially when the heart is stressed, such as during ischemia (29).…”

Section: ␣B-crystallinmentioning

confidence: 99%

Single Molecule Force Spectroscopy of the Cardiac Titin N2B Element

Zhu

Bogomolovas

Labeit

et al. 2009

Journal of Biological Chemistry

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The small heat shock protein ␣B-crystallin interacts with N2B-Us, a large unique sequence found in the N2B element of cardiac titin. Using single molecule force spectroscopy, we studied the effect of ␣B-crystallin on the N2B-Us and its flanking Ig-like domains. Ig domains from the proximal tandem Ig segment of titin were also studied. The effect of wild type ␣B-crystallin on the single molecule force-extension curve was determined as well as that of mutant ␣B-crystallins harboring the dilated cardiomyopathy missense mutation, R157H, or the desmin-related myopathy mutation, R120G. Results revealed that wild type ␣B-crystallin decreased the persistence length of the N2B-Us (from ϳ0.7 to ϳ0.2 nm) but did not alter its contour length. ␣B-crystallin also increased the unfolding force of the Ig domains that flank the N2B-Us (by 51 ؎ 3 piconewtons); the rate constant of unfolding at zero force was estimated to be ϳ17-fold lower in the presence of ␣B-crystallin (1.4 ؋ 10 ؊4 s ؊1 versus 2.4 ؋ 10 ؊3 s ؊1 ). We also found that ␣B-crystallin increased the unfolding force of Ig domains from the proximal tandem Ig segment by 28 ؎ 6 piconewtons. The effects of ␣B-crystallin were attenuated by the R157H mutation (but were still significant) and were absent when using the R120G mutant. We conclude that ␣B-crystallin protects titin from damage by lowering the persistence length of the N2B-Us and reducing the Ig domain unfolding probability. Our finding that this effect is either attenuated (R157H) or lost (R120G) in disease causing ␣B-crystallin mutations suggests that the interaction between ␣B-crystallin and titin is important for normal heart function.␣B-crystallin is a member of the small heat shock protein family that by inhibiting denaturation and aggregation of proteins functions as a molecular chaperone (1). Although ␣B-crystallin has been most intensively studied in the vertebrate eye lens, it is also found in many other tissues (2) with cardiac muscle expressing ␣B-crystallin at 3-5% of the total soluble protein (3). Up-regulation of ␣B-crystallin occurs in a number of cardiac disorders, including familial cardiac hypertrophy, and overexpression appears to protect the cardiac cell from ischemia reperfusion injury (for a review see Ref. 4). An important binding partner of ␣B-crystallin in cardiac muscle is titin (5, 6). Titin is a large filamentous protein that forms a continuous filament along the myofibril, with single titin molecules spanning from the edge to the middle of the sarcomere, a distance of ϳ1 m (7). The I-band region of titin is extensible and functions as a molecular spring that, when extended, develops force (8, 9). This force is an important determinant of the passive stiffness of the heart that determines the filling characteristics during the diastolic part of the heart cycle (10). The interaction between ␣B-crystallin and titin could be important for maintaining heart function, especially when stressed, such as during ischemia (5), warranting studies of the effect of ␣B-crystallin on the biomechanica...

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“…Titin properties can also be modulated in short term by post-translational modification of the elastic I-band domains N2-B unique sequence (N2-Bus) and PEVK (titin domain rich in proline, glutamate, valine, and lysine). Phosphorylation within the cardiac-specific N2-Bus by cAMP-dependent protein kinase, cGMP-dependent protein kinase, extracellular signal-regulated kinase 1/2 (Erk1/2), and Ca 2+ /calmodulin-dependent protein kinase II delta (CaMKIIδ) decreases titin-based cardiac myocyte stiffness, [13][14][15][16][17][18] whereas phosphorylation of the PEVK domain by Ca…”

mentioning

confidence: 99%

Titin-Based Cardiac Myocyte Stiffening Contributes to Early Adaptive Ventricular Remodeling After Myocardial Infarction

Kötter

Kazmierowska

Andresen

et al. 2016

Circulation Research

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Rationale: Myocardial infarction (MI) increases the wall stress in the viable myocardium and initiates early adaptive remodeling in the left ventricle to maintain cardiac output. Later remodeling processes include fibrotic reorganization that eventually leads to cardiac failure. Understanding the mechanisms that support cardiac function in the early phase post MI and identifying the processes that initiate transition to maladaptive remodeling are of major clinical interest. Objective: To characterize MI-induced changes in titin-based cardiac myocyte stiffness and to elucidate the role of titin in ventricular remodeling of remote myocardium in the early phase after MI. Methods and Results: Titin properties were analyzed in Langendorff-perfused mouse hearts after 20-minute ischemia/60-minute reperfusion (I/R), and mouse hearts that underwent ligature of the left anterior descending coronary artery for 3 or 10 days. Cardiac myocyte passive tension was significantly increased 1 hour after ischemia/reperfusion and 3 and 10 days after left anterior descending coronary artery ligature. The increased passive tension was caused by hypophosphorylation of the titin N2-B unique sequence and hyperphosphorylation of the PEVK (titin domain rich in proline, glutamate, valine, and lysine) region of titin. Blocking of interleukine-6 before left anterior descending coronary artery ligature restored titin-based myocyte tension after MI, suggesting that MI-induced titin stiffening is mediated by elevated levels of the cytokine interleukine-6. We further demonstrate that the early remodeling processes 3 days after MI involve accelerated titin turnover by the ubiquitin–proteasome system. Conclusions: We conclude that titin-based cardiac myocyte stiffening acutely after MI is partly mediated by interleukine-6 and is an important mechanism of remote myocardium to adapt to the increased mechanical demands after myocardial injury.

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Protein Kinase G Modulates Human Myocardial Passive Stiffness by Phosphorylation of the Titin Springs

Cited by 358 publications

References 40 publications

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Single Molecule Force Spectroscopy of the Cardiac Titin N2B Element

Titin-Based Cardiac Myocyte Stiffening Contributes to Early Adaptive Ventricular Remodeling After Myocardial Infarction

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