Aldosterone Induces Elastin Production in Cardiac Fibroblasts through Activation of Insulin-Like Growth Factor-I Receptors in a Mineralocorticoid Receptor-Independent Manner

Bunda, Severa; Liu, Peter; Wang, Yanting; Liu, Kela; Hinek, Aleksander

doi:10.2353/ajpath.2007.070101

Cited by 37 publications

(24 citation statements)

References 72 publications

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“…Regarding elastin production, in primary rat VSMC cultures, Aldo induces elastin deposition in an MR and Gal-3 independent manner. This result is in accordance with previous studies that describe Aldo-induced elastogenesis as not dependent on MR. 45 Thus, our current findings provide a new mechanism MR and Gal-3 dependent underlying vascular fibrosis and remodeling caused by Aldo.…”

Section: Discussionmentioning

confidence: 57%

Galectin-3 Mediates Aldosterone-Induced Vascular Fibrosis

Calvier

Miana

Reboul

et al. 2013

ATVB

326

278

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Objective-Aldosterone (Aldo) is involved in arterial stiffness and heart failure, but the mechanisms have remained unclear. Galectin-3 (Gal-3), a β-galactoside-binding lectin, plays an important role in inflammation, fibrosis, and heart failure. We investigated here whether Gal-3 is involved in Aldo-induced vascular fibrosis. Methods and Results-In rat vascular smooth muscle cells Gal-3 overexpression enhanced specifically collagen type I synthesis. Moreover Gal-3 inhibition by modified citrus pectin or small interfering RNA blocked Aldo-induced collagen type I synthesis. Rats were treated with Aldo-salt combined with spironolactone or modified citrus pectin for 3 weeks. Hypertensive Aldo-treated rats presented vascular hypertrophy, inflammation, fibrosis, and increased aortic Gal-3 expression. Spironolactone or modified citrus pectin treatment reversed all the above effects. Wild-type and Gal-3 knockout mice were treated with Aldo for 6 hours or 3 weeks. Aldo increased aortic Gal-3 expression, inflammation, and collagen type I in wild-type mice at both the short-and the long-term, whereas no changes occurred in Gal-3 knock-out mice. Conclusion-Our data indicate that

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Section: Discussionmentioning

confidence: 57%

Galectin-3 Mediates Aldosterone-Induced Vascular Fibrosis

Calvier

Miana

Reboul

et al. 2013

ATVB

326

278

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“…98 Aldosterone increases elastin mRNA levels, tropoelastin synthesis, and elastic fiber deposition in a dose-dependent manner. 99 The elastogenic effect of aldosterone is mediated via a mineralocorticoid receptor-independent mechanism involving insulinlike growth factor-1 receptor signaling. 100 Glucocorticoids upregulate tropoelastin expression in the fetal lung, 101 possibly via a similar corticosteroid pathway.…”

Section: Developing Therapiesmentioning

confidence: 99%

Cardiovascular Disease in Williams Syndrome

2013

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“…We discovered that aldosterone can stimulate elastogenesis in cultures of human cardiac fibroblasts via an MR-independent mechanism involving IGF-IR activation (18). We have therefore uncovered another level of complexity in which aldosterone in conjunction with MR antagonists may modulate the remodeling of the injured heart.…”

mentioning

confidence: 96%

Aldosterone Stimulates Elastogenesis in Cardiac Fibroblasts via Mineralocorticoid Receptor-independent Action Involving the Consecutive Activation of Gα13, c-Src, the Insulin-like Growth Factor-I Receptor, and Phosphatidylinositol 3-Kinase/Akt

Bunda

Wang

Mitts

et al. 2009

Journal of Biological Chemistry

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We previously demonstrated that aldosterone, which stimulates collagen production through the mineralocorticoid receptor (MR)-dependent pathway, also induces elastogenesis via a parallel MR-independent mechanism involving insulin-like growth factor-I receptor (IGF-IR) signaling. The present study provides a more detailed explanation of this signaling pathway. Our data demonstrate that small interfering RNA-driven elimination of MR in cardiac fibroblasts does not inhibit aldosterone-induced IGF-IR phosphorylation and subsequent increase in elastin production. These results exclude the involvement of the MR in aldosterone-induced increases in elastin production. Results of further experiments aimed at identifying the upstream signaling component(s) that might be activated by aldosterone also eliminate the putative involvement of pertussis toxin-sensitive G␣ i proteins, which have previously been shown to be responsible for some MR-independent effects of aldosterone. Instead, we found that small interfering RNA-dependent elimination of another heterotrimeric G protein, G␣ 13 , eliminates aldosterone-induced elastogenesis. We further demonstrate that aldosterone first engages G␣ 13 and then promotes its transient interaction with c-Src, which constitutes a prerequisite step for aldosterone-dependent activation of the IGF-IR and propagation of consecutive downstream elastogenic signaling involving phosphatidylinositol 3-kinase/Akt. In summary, the data we present reveal new details of an MR-independent cellular signaling pathway through which aldosterone stimulates elastogenesis in human cardiac fibroblasts.

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Aldosterone Induces Elastin Production in Cardiac Fibroblasts through Activation of Insulin-Like Growth Factor-I Receptors in a Mineralocorticoid Receptor-Independent Manner

Cited by 37 publications

References 72 publications

Galectin-3 Mediates Aldosterone-Induced Vascular Fibrosis

Galectin-3 Mediates Aldosterone-Induced Vascular Fibrosis

Cardiovascular Disease in Williams Syndrome

Aldosterone Stimulates Elastogenesis in Cardiac Fibroblasts via Mineralocorticoid Receptor-independent Action Involving the Consecutive Activation of Gα13, c-Src, the Insulin-like Growth Factor-I Receptor, and Phosphatidylinositol 3-Kinase/Akt

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