Atrial natriuretic polypeptide inhibits hypertrophy of vascular smooth muscle cells

Hiroshi Itoh, Richard E. Pratt, Victor J. Dzau

Research output: Contribution to journalArticle

286 Citations (Scopus)

Abstract

Vascular remodeling is central to the pathophysiology of hypertension and atherosclerosis. Recent evidence suggests that vasoconstrictive substances, such as angiotensin II (AII), may function as a vascular smooth muscle growth promoting substance. To explore the role of the counterregulatory hormone, atrial natriuretic polypeptide (ANP) in this process, we examined the effect of ANP (alpha-rat ANP [1-28]) on the growth characteristics of cultured rat aortic smooth muscle (RASM) cells. ANP (10-7 M) significantly suppressed the proliferative effect of 1% and 5% serum as measured by 3H-thymidine incorporation and cell number, confirming ANP as an antimitogenic factor. In quiescent RASM cells, ANP (10-7, 10-6 M) significantly suppressed the basal incorporations of 3H-uridine and leucine by 50 and 30%, respectively. ANP (10-7, 10-6 M) also suppressed All-induced RNA and protein syntheses (by 30-40%) with the concomitant reduction of the cell size. Furthermore, ANP also significantly attenuated the increase of 3H-uridine and leucine incorporations caused by transforming growth factor-β (4 × 10-11, 4 × 10-10 M), a potent hypertrophic factor. These results indicate that ANP possesses an antihypertrophic action on vascular smooth muscle cells. Down-regulation of protein kinase C by 24-h treatment with phorbol 12,13-dibutyrate did not inhibit ANP-induced suppression on 3H-uridine incorporation. Based on the observation that ANP was more potent than a ring-deleted analogue of ANP on inhibiting 3H-uridine incorporation, we conclude that the ANP's inhibitory effect is primarily mediated via the activation of a guanylate cyclase-linked ANP receptor(s). Indeed 8-bromo cGMP mimicked the antihypertrophic action of ANP. Accordingly, we speculate that in addition to its vasorelaxant and natriuretic effects, the antihypertrophic action of ANP observed in the present study may serve as an additional compensatory mechanism of ANP in hypertension.

Original languageEnglish
Pages (from-to)1690-1697
Number of pages8
JournalJournal of Clinical Investigation
Volume86
Issue number5
Publication statusPublished - 1990 Nov
Externally publishedYes

Fingerprint

Vascular Smooth Muscle
Hypertrophy
Smooth Muscle Myocytes
Peptides
Uridine
Natriuretic Agents
Leucine
Growth Substances
Phorbol 12,13-Dibutyrate
Hypertension
Guanylate Cyclase
Transforming Growth Factors
Atrial Natriuretic Factor
Vasodilator Agents
Cell Size
Angiotensin II
Thymidine
Protein Kinase C
Atherosclerosis

Keywords

  • Angiotensin II
  • Cyclic GMP
  • Growth factor
  • Hypertension
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Atrial natriuretic polypeptide inhibits hypertrophy of vascular smooth muscle cells. / Itoh, Hiroshi; Pratt, Richard E.; Dzau, Victor J.

In: Journal of Clinical Investigation, Vol. 86, No. 5, 11.1990, p. 1690-1697.

Research output: Contribution to journalArticle

Itoh, Hiroshi ; Pratt, Richard E. ; Dzau, Victor J. / Atrial natriuretic polypeptide inhibits hypertrophy of vascular smooth muscle cells. In: Journal of Clinical Investigation. 1990 ; Vol. 86, No. 5. pp. 1690-1697.
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AB - Vascular remodeling is central to the pathophysiology of hypertension and atherosclerosis. Recent evidence suggests that vasoconstrictive substances, such as angiotensin II (AII), may function as a vascular smooth muscle growth promoting substance. To explore the role of the counterregulatory hormone, atrial natriuretic polypeptide (ANP) in this process, we examined the effect of ANP (alpha-rat ANP [1-28]) on the growth characteristics of cultured rat aortic smooth muscle (RASM) cells. ANP (10-7 M) significantly suppressed the proliferative effect of 1% and 5% serum as measured by 3H-thymidine incorporation and cell number, confirming ANP as an antimitogenic factor. In quiescent RASM cells, ANP (10-7, 10-6 M) significantly suppressed the basal incorporations of 3H-uridine and leucine by 50 and 30%, respectively. ANP (10-7, 10-6 M) also suppressed All-induced RNA and protein syntheses (by 30-40%) with the concomitant reduction of the cell size. Furthermore, ANP also significantly attenuated the increase of 3H-uridine and leucine incorporations caused by transforming growth factor-β (4 × 10-11, 4 × 10-10 M), a potent hypertrophic factor. These results indicate that ANP possesses an antihypertrophic action on vascular smooth muscle cells. Down-regulation of protein kinase C by 24-h treatment with phorbol 12,13-dibutyrate did not inhibit ANP-induced suppression on 3H-uridine incorporation. Based on the observation that ANP was more potent than a ring-deleted analogue of ANP on inhibiting 3H-uridine incorporation, we conclude that the ANP's inhibitory effect is primarily mediated via the activation of a guanylate cyclase-linked ANP receptor(s). Indeed 8-bromo cGMP mimicked the antihypertrophic action of ANP. Accordingly, we speculate that in addition to its vasorelaxant and natriuretic effects, the antihypertrophic action of ANP observed in the present study may serve as an additional compensatory mechanism of ANP in hypertension.

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