Activation of protein kinase A by atrial natriuretic peptide in neonatal rat cardiac fibroblasts: Role in regulation of the local renin-angiotensin system

Sanghi, Sandhya; Kumar, Rajesh; Smith, Manuela; Baker, Kenneth M.; Dostal, David E.

doi:10.1016/j.regpep.2005.06.007

Cited by 27 publications

(22 citation statements)

References 27 publications

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“…Although cardiac myocytes represent the bulk of the myocardial volume, cardiac fibroblasts are the most numerous cell types in the heart and play an essential role in myocardial function. Previously we have demonstrated the expression of Ao in cardiac fibroblasts and its upregulation in different pathological conditions [38-40]. Although there is differential expression of mechanoreceptors in cardiac myocytes and fibroblasts [41], it was interesting to note that similar molecular mechanisms of Ao gene regulation occur at the MAP kinase level in both types of cardiac cells in response to mechanical stretch.…”

Section: Discussionmentioning

confidence: 99%

Stretch-induced regulation of angiotensinogen gene expression in cardiac myocytes and fibroblasts: Opposing roles of JNK1/2 and p38α MAP kinases

Lal

Verma

Golden

et al. 2008

Journal of Molecular and Cellular Cardiology

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The cardiac renin-angiotensin system (RAS) has been implicated in mediating myocyte hypertrophy, remodeling, and fibroblast proliferation in the hemodynamically overloaded heart. However, the intracellular signaling mechanisms responsible for regulation of angiotensinogen (Ao), a substrate of the RAS system, are largely unknown. Here we report the identification of JNK1/2 as a negative, and p38α as a major positive regulator of Ao gene expression. Isolated neonatal rat ventricular myocytes (NRVM) and fibroblasts (NRFB) plated on deformable membranes coated with collagen IV, were exposed to 20% equiaxial static-stretch (0-24 hr). Mechanical stretch initially depressed Ao gene expression (4 h), whereas after 8 h, Ao gene expression increased in a time-dependent manner. Blockade of JNK1/2 with SP600125 increased basal Ao gene expression in NRVM (10.52 ± 1.98 fold, P<0.001) and NRFB (13.32 ± 2.07 fold, P<0.001). Adenovirus-mediated expression of wild-type JNK1 significantly inhibited, whereas expression of dominant-negative JNK1 and JNK2 increased basal and stretch-mediated (24 h) Ao gene expression, showing that both JNK1 and JNK2 to be negative regulators of Ao gene expression in NRVM and NRFB. Blockade of p38α/β by SB202190 or p38α by SB203580 significantly inhibited stretch-induced (24 h) Ao gene expression, whereas expression of wild-type p38α increased stretch-induced Ao gene expression in both NRVM (8.41 ± 1.50 fold, P<0.001) and NRFB (3.39 ± 0.74 fold, P<0.001). Conversely, expression of dominant-negative p38α significantly inhibited stretch response. Moreover, expression of constitutively active MKK6b (E) significantly stimulated Ao gene expression in absence of stretch, indicating that p38 activation alone is sufficient to induce Ao gene expression. Taken together p38α was demonstrated to be a positive regulator, whereas JNK1/2 was found to be a negative regulator of Ao gene expression. Prolonged stretch diminished JNK1/2 activation, which was accompanied by a reciprocal increase in p38 activation and Ao gene expression. This suggests that a balance in JNK1/2 and p38α activation determines the level of Ao gene expression in myocardial cells.

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Section: Discussionmentioning

confidence: 99%

Stretch-induced regulation of angiotensinogen gene expression in cardiac myocytes and fibroblasts: Opposing roles of JNK1/2 and p38α MAP kinases

Lal

Verma

Golden

et al. 2008

Journal of Molecular and Cellular Cardiology

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“…Recently, it has been demonstrated that a local RAS exists in the heart and plays an key role in cardiac function 168, 169 . Cardiac fibroblasts can express angiotensinogen, renin and ACE-1, allowing them to effectively produce Ang II 170 . Moreover, it has been shown that Ang II can increase collagen production and secretion from cardiac fibroblasts, which occurs through the AT1R 171, 172 .…”

Section: Cardiac Fibroblasts and Chemical And Mechanical Signalingmentioning

confidence: 99%

Cardiac Fibroblast

Souders

Bowers

Baudino

2009

Circulation Research

835

481

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The permanent cellular constituents of the heart include cardiac fibroblasts, myocytes, endothelial cells and vascular smooth muscle cells. Previous studies have demonstrated that there are undulating changes in cardiac cell populations during embryonic development, through neonatal development and into the adult. Transient cell populations include lymphocytes, mast cells and macrophages, which can interact with these permanent cell types to affect cardiac function. It has also been observed that there are marked differences in the makeup of the cardiac cell populations depending on the species, which may be important when examining myocardial remodeling. Current dogma states that the fibroblast makes up the largest cell population of the heart; however, this appears to vary for different species, especially mice. Cardiac fibroblasts play a critical role in maintaining normal cardiac function, as well as in cardiac remodeling during pathological conditions such as myocardial infarct and hypertension. These cells have numerous functions, including synthesis and deposition of extracellular matrix, cell-cell communication with myocytes, cell-cell signaling with other fibroblasts, as well as with endothelial cells. These contacts affect the electrophysiological properties, secretion of growth factors and cytokines, as well as potentiating blood vessel formation. While a plethora of information is known about several of these processes, relatively little is understood about fibroblasts and their role in angiogenesis during development or cardiac remodeling. In this review we provide insight into the various properties of cardiac fibroblasts that helps illustrate their importance in maintaining proper cardiac function, as well as their critical role in the remodeling heart.

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“…NRVM were exposed for 24, 48, and 72 h to high glucose (25 mM) or isoproterenol (10 M) as described above. Equal amounts of cell lysates or culture medium proteins (30 g) were separated on 4 -20% SDS-polyacrylamide gels and transferred to nitrocellulose membranes as previously described (44,45). Blots were probed with anti-angiotensinogen (Swant), anti-renin (Swant), antichymase (Abcam), or anti-ACE-1 (Abcam) antibody.…”

Section: Enzyme Inhibitionmentioning

confidence: 99%

High-glucose-induced regulation of intracellular ANG II synthesis and nuclear redistribution in cardiac myocytes

Singh¹,

Le²,

Bhat³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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135

138

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The prevailing paradigm is that cardiac ANG II is synthesized in the extracellular space from components of the circulating and/or local renin-angiotensin system. The recent discovery of intracrine effects of ANG II led us to determine whether ANG II is synthesized intracellularly in neonatal rat ventricular myocytes (NRVM). NRVM, incubated in serum-free medium, were exposed to isoproterenol or high glucose in the absence or presence of candesartan, which was used to prevent angiotensin type 1 (AT(1)) receptor-mediated internalization of ANG II. ANG II was measured in cell lysates and the culture medium, which represented intra- and extracellularly synthesized ANG II, respectively. Isoproterenol increased ANG II concentration in cell lysates and medium of NRVM in the absence or presence of candesartan. High glucose markedly increased ANG II synthesis only in cell lysates in the absence and presence of candesartan. Western analysis showed increased intracellular levels of angiotensinogen, renin, and chymase in high-glucose-exposed cells. Confocal immunofluorocytometry confirmed the presence of ANG II in the cytoplasm and nucleus of high-glucose-exposed NRVM and along the actin filaments in isoproterenol-exposed cells. ANG II synthesis was dependent on renin and chymase in high-glucose-exposed cells and on renin and angiotensin-converting enzyme in isoproterenol-exposed cells. In summary, the site of ANG II synthesis, intracellular localization, and the synthetic pathway in NRVM are stimulus dependent. Significantly, NRVM synthesized and retained ANG II intracellularly, which redistributed to the nucleus under high-glucose conditions, suggesting a role for an intracrine mechanism in diabetic conditions.

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Activation of protein kinase A by atrial natriuretic peptide in neonatal rat cardiac fibroblasts: Role in regulation of the local renin-angiotensin system

Cited by 27 publications

References 27 publications

Stretch-induced regulation of angiotensinogen gene expression in cardiac myocytes and fibroblasts: Opposing roles of JNK1/2 and p38α MAP kinases

Stretch-induced regulation of angiotensinogen gene expression in cardiac myocytes and fibroblasts: Opposing roles of JNK1/2 and p38α MAP kinases

Cardiac Fibroblast

High-glucose-induced regulation of intracellular ANG II synthesis and nuclear redistribution in cardiac myocytes

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