Myocardial fibrosis associated with aldosterone or angiotensin II administration

Attenuation by calcium channel blockade

Felix J.A. Ramires, Yao Sun, Karl Weber

Research output: Contribution to journalArticle

113 Citations (Scopus)

Abstract

Chronic administration of either angiotensin II (Ang II) or aldosterone (ALDO) leads to myocardial fibrosis. Myofibroblasts (myoFb) play a major role in collagen accumulation at sites of tissue repair. Pathophysiologic bases of cardiac fibrosis in such chronic primary or secondary hyperaldosteronism are under investigation. In vitro studies have shown that Ang II and ALDO each increase intracellular calcium and this second messenger is involved in altered fibroblast collagen turnover and growth. In the present study, we tested our hypothesis that calcium channel blockade would attenuate myocardial fibrosis that accompanies administration of either circulating Ang II or ALDO. Five animal groups were studied: (1) untreated age- and sex-matched control rats; (2) intact rats receiving Ang II (75 ng/min) for 2 weeks; (3) rats receiving Ang II plus mibefradil (30 mg/kg/day p.o.), a calcium channel blocker, for 2 weeks; (4) uninephrectomized rats receiving ALDO (0.75 μg/h) together with a high salt diet for 6 weeks; and () uninephrectomized rats receiving ALDO and high salt diet plus mibefradil. Myocardial fibrosis was assessed by hydroxyproline concentration and interstitial and perivascular collagen volume fraction examined by videodensitometry on heart sections stained with collagen-specific picrosirius red. MyoFb were identified by immunohistochemical α-smooth muscle actin (SMA) labeling. ACE binding was determined by in vitro quantitative autoradiography. Compared to controls, in rats receiving either Ang II or ALDO we found: (1) myocardial fibrosis, expressed as microscopic scars, and perivascular fibrosis in both right and left ventricles with increased (P < 0.05) hydroxyproline concentration and collagen volume fraction; (2) myoFb at sites of fibrosis, where high ACE binding density was also present; and (3) hydroxyproline concentration and collagen volume fraction were significantly (P < 0.05) attenuated and the extent of α-SMA labeling and ACE binding density were each markedly (P < 0.01) reduced in rats receiving either hormone plus mibefradil. This study therefore suggests calcium may modulate fibrous tissue formation in rat models of hyperaldosteronism by altering MyoFb collagen turnover and cell growth. It further is our contention that these findings implicate calcium as a signal used by effector hormones of the RAAS to promote tissue repair and that calcium channel blockade may offer advantage as a cardioprotective strategy in this setting.

Original languageEnglish (US)
Pages (from-to)475-483
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume30
Issue number3
DOIs
StatePublished - Jan 1 1998
Externally publishedYes

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Calcium Channels
Aldosterone
Angiotensin II
Fibrosis
Collagen
Mibefradil
Hyperaldosteronism
Myofibroblasts
Hydroxyproline
Calcium
Heart Ventricles
Smooth Muscle
Actins
Salts
Hormones
Diet
Calcium Channel Blockers
Second Messenger Systems
Growth
Autoradiography

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

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title = "Myocardial fibrosis associated with aldosterone or angiotensin II administration: Attenuation by calcium channel blockade",
abstract = "Chronic administration of either angiotensin II (Ang II) or aldosterone (ALDO) leads to myocardial fibrosis. Myofibroblasts (myoFb) play a major role in collagen accumulation at sites of tissue repair. Pathophysiologic bases of cardiac fibrosis in such chronic primary or secondary hyperaldosteronism are under investigation. In vitro studies have shown that Ang II and ALDO each increase intracellular calcium and this second messenger is involved in altered fibroblast collagen turnover and growth. In the present study, we tested our hypothesis that calcium channel blockade would attenuate myocardial fibrosis that accompanies administration of either circulating Ang II or ALDO. Five animal groups were studied: (1) untreated age- and sex-matched control rats; (2) intact rats receiving Ang II (75 ng/min) for 2 weeks; (3) rats receiving Ang II plus mibefradil (30 mg/kg/day p.o.), a calcium channel blocker, for 2 weeks; (4) uninephrectomized rats receiving ALDO (0.75 μg/h) together with a high salt diet for 6 weeks; and () uninephrectomized rats receiving ALDO and high salt diet plus mibefradil. Myocardial fibrosis was assessed by hydroxyproline concentration and interstitial and perivascular collagen volume fraction examined by videodensitometry on heart sections stained with collagen-specific picrosirius red. MyoFb were identified by immunohistochemical α-smooth muscle actin (SMA) labeling. ACE binding was determined by in vitro quantitative autoradiography. Compared to controls, in rats receiving either Ang II or ALDO we found: (1) myocardial fibrosis, expressed as microscopic scars, and perivascular fibrosis in both right and left ventricles with increased (P < 0.05) hydroxyproline concentration and collagen volume fraction; (2) myoFb at sites of fibrosis, where high ACE binding density was also present; and (3) hydroxyproline concentration and collagen volume fraction were significantly (P < 0.05) attenuated and the extent of α-SMA labeling and ACE binding density were each markedly (P < 0.01) reduced in rats receiving either hormone plus mibefradil. This study therefore suggests calcium may modulate fibrous tissue formation in rat models of hyperaldosteronism by altering MyoFb collagen turnover and cell growth. It further is our contention that these findings implicate calcium as a signal used by effector hormones of the RAAS to promote tissue repair and that calcium channel blockade may offer advantage as a cardioprotective strategy in this setting.",
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T1 - Myocardial fibrosis associated with aldosterone or angiotensin II administration

T2 - Attenuation by calcium channel blockade

AU - Ramires, Felix J.A.

AU - Sun, Yao

AU - Weber, Karl

PY - 1998/1/1

Y1 - 1998/1/1

N2 - Chronic administration of either angiotensin II (Ang II) or aldosterone (ALDO) leads to myocardial fibrosis. Myofibroblasts (myoFb) play a major role in collagen accumulation at sites of tissue repair. Pathophysiologic bases of cardiac fibrosis in such chronic primary or secondary hyperaldosteronism are under investigation. In vitro studies have shown that Ang II and ALDO each increase intracellular calcium and this second messenger is involved in altered fibroblast collagen turnover and growth. In the present study, we tested our hypothesis that calcium channel blockade would attenuate myocardial fibrosis that accompanies administration of either circulating Ang II or ALDO. Five animal groups were studied: (1) untreated age- and sex-matched control rats; (2) intact rats receiving Ang II (75 ng/min) for 2 weeks; (3) rats receiving Ang II plus mibefradil (30 mg/kg/day p.o.), a calcium channel blocker, for 2 weeks; (4) uninephrectomized rats receiving ALDO (0.75 μg/h) together with a high salt diet for 6 weeks; and () uninephrectomized rats receiving ALDO and high salt diet plus mibefradil. Myocardial fibrosis was assessed by hydroxyproline concentration and interstitial and perivascular collagen volume fraction examined by videodensitometry on heart sections stained with collagen-specific picrosirius red. MyoFb were identified by immunohistochemical α-smooth muscle actin (SMA) labeling. ACE binding was determined by in vitro quantitative autoradiography. Compared to controls, in rats receiving either Ang II or ALDO we found: (1) myocardial fibrosis, expressed as microscopic scars, and perivascular fibrosis in both right and left ventricles with increased (P < 0.05) hydroxyproline concentration and collagen volume fraction; (2) myoFb at sites of fibrosis, where high ACE binding density was also present; and (3) hydroxyproline concentration and collagen volume fraction were significantly (P < 0.05) attenuated and the extent of α-SMA labeling and ACE binding density were each markedly (P < 0.01) reduced in rats receiving either hormone plus mibefradil. This study therefore suggests calcium may modulate fibrous tissue formation in rat models of hyperaldosteronism by altering MyoFb collagen turnover and cell growth. It further is our contention that these findings implicate calcium as a signal used by effector hormones of the RAAS to promote tissue repair and that calcium channel blockade may offer advantage as a cardioprotective strategy in this setting.

AB - Chronic administration of either angiotensin II (Ang II) or aldosterone (ALDO) leads to myocardial fibrosis. Myofibroblasts (myoFb) play a major role in collagen accumulation at sites of tissue repair. Pathophysiologic bases of cardiac fibrosis in such chronic primary or secondary hyperaldosteronism are under investigation. In vitro studies have shown that Ang II and ALDO each increase intracellular calcium and this second messenger is involved in altered fibroblast collagen turnover and growth. In the present study, we tested our hypothesis that calcium channel blockade would attenuate myocardial fibrosis that accompanies administration of either circulating Ang II or ALDO. Five animal groups were studied: (1) untreated age- and sex-matched control rats; (2) intact rats receiving Ang II (75 ng/min) for 2 weeks; (3) rats receiving Ang II plus mibefradil (30 mg/kg/day p.o.), a calcium channel blocker, for 2 weeks; (4) uninephrectomized rats receiving ALDO (0.75 μg/h) together with a high salt diet for 6 weeks; and () uninephrectomized rats receiving ALDO and high salt diet plus mibefradil. Myocardial fibrosis was assessed by hydroxyproline concentration and interstitial and perivascular collagen volume fraction examined by videodensitometry on heart sections stained with collagen-specific picrosirius red. MyoFb were identified by immunohistochemical α-smooth muscle actin (SMA) labeling. ACE binding was determined by in vitro quantitative autoradiography. Compared to controls, in rats receiving either Ang II or ALDO we found: (1) myocardial fibrosis, expressed as microscopic scars, and perivascular fibrosis in both right and left ventricles with increased (P < 0.05) hydroxyproline concentration and collagen volume fraction; (2) myoFb at sites of fibrosis, where high ACE binding density was also present; and (3) hydroxyproline concentration and collagen volume fraction were significantly (P < 0.05) attenuated and the extent of α-SMA labeling and ACE binding density were each markedly (P < 0.01) reduced in rats receiving either hormone plus mibefradil. This study therefore suggests calcium may modulate fibrous tissue formation in rat models of hyperaldosteronism by altering MyoFb collagen turnover and cell growth. It further is our contention that these findings implicate calcium as a signal used by effector hormones of the RAAS to promote tissue repair and that calcium channel blockade may offer advantage as a cardioprotective strategy in this setting.

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