Cardiomyocyte-restricted restoration of nitric oxide synthase 3 attenuates left ventricular remodeling after chronic pressure overload

Buys, Emmanuel; Raher, Michael J.; Blake, Sarah L.; Neilan, Tomas G.; Graveline, Amanda; Passeri, Jonathan J.; Llano, Miguel; Pérez-Sanz, Teresa M.; Ichinose, Fumito; Janssens, Stefan; Zapol, Warren M.; Picard, Michael H.; Bloch, Kenneth D.; Scherrer‐Crosbie, Marielle

doi:10.1152/ajpheart.01236.2006

Cited by 67 publications

(45 citation statements)

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“…This deviates from previous reports where cardiac myocyte-specific restoration of eNOS expression in NOS3 −/− mice did not attenuate fibrosis in response to TAC 39 and mice with a cardiac myocytespecific eNOS transgene also exhibited unchanged fibrosis in the remote myocardium after MI. 34 This suggests that the systemic NOS inhibition with L-NAME in our experiments abrogated the modulation of profibrotic cytokines by NOS in neighboring cells (eg, endothelial cells) rather than in cardiac myocytes.…”

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confidence: 99%

Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase

et al. 2014

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451H emodynamic overload and ischemic or oxidative stress promote adverse cardiac remodeling, a leading cause of worsening heart failure.1,2 Most of these pathophysiologic conditions are associated with (and to a certain extent, mediated by) adrenergic stimulation and catecholamines release, resulting in adrenoceptor (AR) activation on different cell types within the myocardium. Among these, cardiac myocyte β1-ARs are classically considered to mediate short-term positive effects on all aspects of myocardial contractility; however, long-term stimulation produces adverse effects on myocardial remodeling, in part through activation of calciumdependent prohypertrophic effects, ultimately associated with cardiomyocyte loss. 3,4 Such maladaptive remodeling is usually accompanied by left ventricle (LV) geometry disruption Background-β1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. β3-AR expression is enhanced in diseased human myocardium, but its impact on remodeling is unknown. Methods and Results-Mice with cardiac myocyte-specific expression of human β3-AR (β3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). β3-TG and WT had similar morphometric and hemodynamic parameters at baseline. β3-AR colocalized with caveolin-3, endothelial nitric oxide synthase (NOS) and neuronal NOS in adult transgenic myocytes, which constitutively produced more cyclic GMP, detected with a new transgenic FRET sensor. Iso and Ang II produced hypertrophy and fibrosis in WT mice, but not in β3-TG mice, which also had less re-expression of fetal genes and transforming growth factor β1.Protection from Iso-induced hypertrophy was reversed by nonspecific NOS inhibition at low dose Iso, and by preferential neuronal NOS inhibition at high-dose Iso. Adenoviral overexpression of β3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine. Hypertrophy was restored on NOS or protein kinase G inhibition. Mechanistically, β3-AR overexpression inhibited phenylephrine-induced nuclear factor of activated T-cell activation. Conclusions-Cardiac-specific overexpression of β3-AR does not affect cardiac morphology at baseline but inhibits the hypertrophic response to neurohormonal stimulation in vivo and in vitro, through a NOS-mediated mechanism. Activation of the cardiac β3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling. and interstitial and replacement fibrosis leading to progressive diastolic and systolic heart failure. Deciphering the underlying signaling pathways may lead to new therapeutic strategies that favorably modulate remodeling. The use of β1-AR blockers provided a major advance in this direction, albeit far from totally efficient. 5 The third isotype of β-AR (β3-AR) has classically been considered as a metabolic regulator (eg, by mediating lipolysis in the adipose tissue).6 β3-ARs ...

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Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase

et al. 2014

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“…A study found that, after chronic pressure overload, NOS3 Ϫ/Ϫ mice had increased hypertrophy, fibrosis, and contractile dysfunction compared with WT mice (41). In addition, mice with cardiac myocyte-specific NOS3 overexpression had limited hypertrophy and contractile dysfunction after pressure overload and myocardial infarction (10,23). Furthermore, it is known that I Ca plays a role in hypertrophy (14).…”

Section: Nos3 and Arrhythmogenesismentioning

confidence: 99%

Endothelial nitric oxide synthase decreases β-adrenergic responsiveness via inhibition of the L-type Ca²⁺ current

Wang

Kohr

Wheeler

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…Abundant evidence suggests that nitric oxide (NO) has critical roles in the regulation of myocardial function and structure (5,24,48) and blood pressure (23,50). NO plays a pivotal role in cytokine-induced myocardial dysfunction (17,30,52), either attenuating or exacerbating the adverse hemodynamic sequelae associated with systemic inflammation.…”

mentioning

confidence: 99%

sGCα₁β₁attenuates cardiac dysfunction and mortality in murine inflammatory shock models

Buys¹,

Cauwels²,

Raher³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Buys ES, Cauwels A, Raher MJ, Passeri JJ, Hobai I, Cawley SM, Rauwerdink KM, Thibault H, Sips PY, Thoonen R, ScherrerCrosbie M, Ichinose F, Brouckaert P, Bloch KD. sGC␣ 1␤1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models. Am J Physiol Heart Circ Physiol 297: H654 -H663, 2009. First published June 5, 2009 doi:10.1152/ajpheart.00367.2009.-Altered cGMP signaling has been implicated in myocardial depression, morbidity, and mortality associated with sepsis. Previous studies, using inhibitors of soluble guanylate cyclase (sGC), suggested that cGMP generated by sGC contributed to the cardiac dysfunction and mortality associated with sepsis. We used sGC␣1-deficient (sGC␣ 1 Ϫ/Ϫ ) mice to unequivocally determine the role of sGC␣1␤1 in the development of cardiac dysfunction and death associated with two models of inflammatory shock: endotoxin-and TNF-induced shock. At baseline, echocardiographic assessment and invasive hemodynamic measurements of left ventricular (LV) dimensions and function did not differ between wild-type (WT) mice and sGC␣1 Ϫ/Ϫ mice on the C57BL/6 background (sGC␣ 1 Ϫ/ϪB6 mice). At 14 h after endotoxin challenge, cardiac dysfunction was more pronounced in sGC␣ 1 Ϫ/ϪB6 than WT mice, as assessed using echocardiographic and hemodynamic indexes of LV function. Similarly, Ca 2ϩ handling and cell shortening were impaired to a greater extent in cardiomyocytes isolated from sGC␣ 1 Ϫ/ϪB6 than WT mice after endotoxin challenge. Importantly, morbidity and mortality associated with inflammatory shock induced by endotoxin or TNF were increased in sGC␣1compared with WT mice. Together, these findings suggest that cGMP generated by sGC␣1␤1 protects against cardiac dysfunction and mortality in murine inflammatory shock models. soluble guanylate cyclase; left ventricular function; sepsis; mice; nitric oxide IN THE UNITED STATES, sepsis and septic shock develop in 750,000 people annually, of whom Ͼ210,000 die (1), thereby making sepsis a leading cause of death in intensive care units. Invading microorganisms (including gram-positive and -negative bacteria, viruses, fungi, and parasites) induce the release of a wide variety of proinflammatory mediators, causing a systemic inflammatory response syndrome. Systemic inflammatory response syndrome can develop independently of an infection, for example, in cases of pancreatitis or trauma, as well as after cardiopulmonary bypass. It is recognized that refractory hypotension and myocardial depression contribute significantly to the morbidity and mortality of sepsis and septic shock (33,43,57). Similarly, inflammatory shock induced by TNF is characterized by cardiovascular collapse (8, 34).Abundant evidence suggests that nitric oxide (NO) has critical roles in the regulation of myocardial function and structure (5, 24, 48) and blood pressure (23,50). NO plays a pivotal role in cytokine-induced myocardial dysfunction (17, 30, 52), either attenuating or exacerbating the adverse hemodynamic sequelae associated with systemic inflammation. NO is synthes...

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Cardiomyocyte-restricted restoration of nitric oxide synthase 3 attenuates left ventricular remodeling after chronic pressure overload

Cited by 67 publications

References 27 publications

Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase

Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase

Endothelial nitric oxide synthase decreases β-adrenergic responsiveness via inhibition of the L-type Ca²⁺ current

sGCα₁β₁attenuates cardiac dysfunction and mortality in murine inflammatory shock models

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Cardiomyocyte-restricted restoration of nitric oxide synthase 3 attenuates left ventricular remodeling after chronic pressure overload

Cited by 67 publications

References 27 publications

Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase

Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase

Endothelial nitric oxide synthase decreases β-adrenergic responsiveness via inhibition of the L-type Ca2+ current

sGCα1β1attenuates cardiac dysfunction and mortality in murine inflammatory shock models

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Endothelial nitric oxide synthase decreases β-adrenergic responsiveness via inhibition of the L-type Ca²⁺ current

sGCα₁β₁attenuates cardiac dysfunction and mortality in murine inflammatory shock models