Cardiomyocyte-specific expression of CRNK, the C-terminal domain of PYK2, maintains ventricular function and slows ventricular remodeling in a mouse model of dilated cardiomyopathy

Koshman, Yevgeniya E.; Chu, Miensheng; Kim, Tae-Hoon; Kalmanson, Olivia A.; Farjah, Mariam; Kumar, Mohit; Lewis, William; Geenen, David L.; Tombe, Pieter de; Goldspink, Paul H.; Solaro, R. John; Samarel, Allen M.

doi:10.1016/j.yjmcc.2014.03.021

Cited by 15 publications

(6 citation statements)

References 43 publications

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“…Analysis of upstream signaling pathways revealed that a sustained increase in intracellular Ca 2+ through Orai1 is associated with Pyk2 (a member of the FAK family of protein tyrosine kinases)/MEK/ERK signaling pathway overactivation. This is consistent with upregulation and activation of Pyk2 in the pathogenesis of LVremodeling and HF [41][42][43] and corroborates that in vitro Orai1 silencing or inhibition has been associated with a reduction of ERK1/2 and Pyk2 activity after phenylephrine treatment in neonatal cardiomyocytes 4 and in glioma cells. 44 In addition, cumulative evidence suggests that Pyk2 and ERK1/2 negatively regulate SER-CA2a expression in neonatal, HL-1, and adult cardiomyocytes, 21,23,[45][46][47] and arterial smooth muscle.…”

Section: Original Research Articlesupporting

confidence: 86%

Orai1 channel inhibition preserves left ventricular systolic function and normal Ca2+ handling after pressure overload

Bartoli

Bailey

Rode

et al. 2020

Archives of Cardiovascular Diseases Supplements

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Sources of Funding, see page 214 BACKGROUND: Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca 2+ entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear. METHODS: To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocytespecific expression of an ion pore-disruptive Orai1 R91W mutant (C-dnO1). Synthetic chemistry and channel screening strategies were used to develop 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline (hereafter referred to as JPIII), a small-molecule Orai1 channel inhibitor suitable for in vivo delivery. RESULTS: Adult mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and reduced ventricular function associated with increased Orai1 expression and Orai1-dependent SOCE (assessed by Mn 2+ influx). C-dnO1 mice displayed normal cardiac electromechanical function and cellular excitation-contraction coupling despite reduced Orai1-dependent SOCE. Five weeks after TAC, C-dnO1 mice were protected from systolic dysfunction (assessed by preserved left ventricular fractional shortening and ejection fraction) even if increased cardiac mass and prohypertrophic markers induction were observed. This is correlated with a protection from TAC-induced cellular Ca 2+ signaling alterations (increased SOCE, decreased [Ca 2+ ] i transients amplitude and decay rate, lower SR Ca 2+ load and depressed cellular contractility) and SERCA2a downregulation in ventricular cardiomyocytes from C-dnO1 mice, associated with blunted Pyk2 signaling. There was also less fibrosis in heart sections from C-dnO1 mice after TAC. Moreover, 3 weeks treatment with JPIII following 5 weeks of TAC confirmed the translational relevance of an Orai1 inhibition strategy during hypertrophic insult. CONCLUSIONS: The findings suggest a key role of cardiac Orai1 channels and the potential for Orai1 channel inhibitors as inotropic therapies for maintaining contractility reserve after hypertrophic stress.

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Section: Original Research Articlesupporting

confidence: 86%

Orai1 channel inhibition preserves left ventricular systolic function and normal Ca2+ handling after pressure overload

Bartoli

Bailey

Rode

et al. 2020

Archives of Cardiovascular Diseases Supplements

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“…FG-3149 had no effect on PKCε expression in either FVB or PKCε mice (Online Figure III). FG-3149 also significantly increased (rather than decreased) the enhanced myofilament phosphorylation of cTnI at Thr143 observed in PKCε mice [23], and had no effect on the modestly increased phosphorylation of MyBP-C at Ser302 (Online Figure IV) [24,25]. Nevertheless, the mAb had significant effects in terms of preserving LV function in PKCε mice.…”

Section: Resultsmentioning

confidence: 99%

Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy

Koshman

Sternlicht

Kim

et al. 2015

Journal of Molecular and Cellular Cardiology

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Cardiac structural changes associated with dilated cardiomyopathy (DCM) include cardiomyocyte hypertrophy and myocardial fibrosis. Connective Tissue Growth Factor (CTGF) has been associated with tissue remodeling and is highly expressed in failing hearts. Our aim was to test if inhibition of CTGF would alter the course of cardiac remodeling and preserve cardiac function in the protein kinase Cε (PKCε) mouse model of DCM. Transgenic mice expressing constitutively active PKCε in cardiomyocytes develop cardiac dysfunction that was evident by 3 months of age, and that progressed to cardiac fibrosis, heart failure, and increased mortality. Beginning at 3 months of age, PKCε mice were treated with a neutralizing monoclonal antibody to CTGF (FG-3149) for an additional 3 months. CTGF inhibition significantly improved left ventricular (LV) systolic and diastolic function in PKCε mice, and slowed the progression of LV dilatation. Using gene arrays and quantitative PCR, the expression of many genes associated with tissue remodeling were elevated in PKCε mice, but significantly decreased by CTGF inhibition. However total collagen deposition was not attenuated. The observation of significantly improved LV function by CTGF inhibition in PKCε mice suggests that CTGF inhibition may benefit patients with DCM. Additional studies to explore this potential are warranted.

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“…Myocyte fragments were isolated from frozen LV tissue by mechanical dissociation and chemically permeabilized with 0.3% Triton X-100 and used as described (2,4,22). Active force development was fit to a modified Hill equation that yields maximum force development, Hill coefficient (a measure of cooperativity), and pCa 50 (Ϫlog [Ca 2ϩ ], where 50% of maximum force is developed, a measure of myofilament Ca 2ϩ sensitivity).…”

Section: Methodsmentioning

confidence: 99%

Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

Wilson

Guggilam

West

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Wilson K, Guggilam A, West TA, Zhang X, Trask AJ, Cismowski MJ, de Tombe P, Sadayappan S, Lucchesi PA. Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure. Am J Physiol Heart Circ Physiol 307: H1605-H1617, 2014. First published September 26, 2014 doi:10.1152/ajpheart.00423.2014.-Aortocaval fistula (ACF)-induced volume overload (VO) heart failure (HF) results in progressive left ventricular (LV) dysfunction. Hemodynamic load reversal during pre-HF (4 wk post-ACF; REV) results in rapid structural but delayed functional recovery. This study investigated myocyte and myofilament function in ACF and REV and tested the hypothesis that a myofilament Ca 2ϩ sensitizer would improve VOinduced myofilament dysfunction in ACF and REV. Following the initial sham or ACF surgery in male Sprague-Dawley rats (200 -240 g) at week 0, REV surgery and experiments were performed at weeks 4 and 8, respectively. In ACF, decreased LV function is accompanied by impaired sarcomeric shortening and force generation and decreased Ca 2ϩ sensitivity, whereas, in REV, impaired LV function is accompanied by decreased Ca 2ϩ sensitivity. Intravenous levosimendan (Levo) elicited the best inotropic and lusitropic responses and was selected for chronic oral studies. Subsets of ACF and REV rats were given vehicle (water) or Levo (1 mg/kg) in drinking water from weeks 4 -8. Levo improved systolic (% fractional shortening, end-systolic elastance, and preload-recruitable stroke work) and diastolic (, dP/ dt min) function in ACF and REV. Levo improved Ca 2ϩ sensitivity without altering the amplitude and kinetics of the intracellular Ca 2ϩ transient. In ACF-Levo, increased cMyBP-C Ser-273 and Ser-302 and cardiac troponin I Ser-23/24 phosphorylation correlated with improved diastolic relaxation, whereas, in REV-Levo, increased cMyBP-C Ser-273 phosphorylation and increased ␣-to-␤-myosin heavy chain correlated with improved diastolic relaxation. We concluded that Levo improves LV function, and myofilament composition and regulatory protein phosphorylation likely play a key role in improving function. myofilament dysfunction; myofilament Ca 2ϩ sensitization; levosimendan; myosin-binding protein-C; troponin I MITRAL REGURGITATION (MR) is the most and second most common valve lesion in the United States and Europe, respectively, affecting Ͼ2 million Americans (10, 16). The pathophysiological consequences of MR include chronic left ventricular (LV) hemodynamic volume overload (VO) followed by LV chamber dilation, progressive LV contractile dysfunction, and heart failure (HF). Despite the clinical importance of VO, few models mimic the pathophysiological progression of chronic VO with and without hemodynamic load reduction. The aortocaval fistula (ACF) model of VO HF in the rodent mimics increased hemodynamic preload observed in human disease, irrespective of etiology. In this model, chronically increased LV preload leads to progressive LV pump failure, which is classified into t...

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Cardiomyocyte-specific expression of CRNK, the C-terminal domain of PYK2, maintains ventricular function and slows ventricular remodeling in a mouse model of dilated cardiomyopathy

Cited by 15 publications

References 43 publications

Orai1 channel inhibition preserves left ventricular systolic function and normal Ca2+ handling after pressure overload

Orai1 channel inhibition preserves left ventricular systolic function and normal Ca2+ handling after pressure overload

Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy

Effects of a myofilament calcium sensitizer on left ventricular systolic and diastolic function in rats with volume overload heart failure

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