Universität zu Köln

Keller, Kirsten, Maass, Martina, Dizayee, Sara, Leiss, Veronika, Annala, Suvi, Koeth, Jessica, Seemann, Wiebke K., Mueller-Ehmsen, Jochen, Mohr, Klaus, Nurnberg, Bernd, Engelhardt, Stefan ORCID: 0000-0001-5378-8661, Herzig, Stefan, Birnbaumer, Lutz and Matthes, Jan ORCID: 0000-0003-2754-1555 (2015). Lack of G alpha(i2) leads to dilative cardiomyopathy and increased mortality in beta(1)-adrenoceptor overexpressing mice. Cardiovasc. Res., 108 (3). S. 348 - 357. OXFORD: OXFORD UNIV PRESS. ISSN 1755-3245

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Abstract

Inhibitory G (G(i)) proteins have been proposed to be cardioprotective. We investigated effects of G alpha(i2) knockout on cardiac function and survival in a murine heart failure model of cardiac beta(1)-adrenoceptor overexpression. beta(1)-transgenic mice lacking G alpha(i2) (beta(1)-tg/G alpha(-/-)(i2)) were compared with wild-type mice and littermates either overexpressing cardiac beta(1)-adrenoceptors (beta(1)-tg) or lacking G alpha(i2) (G alpha(-/-)(i2)). At 300 days, mortality of mice only lacking G alpha(i2) was already higher compared with wild-type or beta(1)-tg, but similar to beta(1)-tg/G alpha(-/-)(i2), mice. Beyond 300 days, mortality of beta(1)-tg/G alpha(-/-)(i2) mice was enhanced compared with all other genotypes (mean survival time: 363 +/- 21 days). At 300 days of age, echocardiography revealed similar cardiac function of wild-type, beta(1)-tg, and G alpha(-/-)(i2) mice, but significant impairment for beta(1)-tg/G alpha(-/-)(i2) mice (e.g. ejection fraction 14 +/- 2 vs. 40 +/- 4% in wild-type mice). Significantly increased ventricle-to-body weight ratio (0.71 +/- 0.06 vs. 0.48 +/- 0.02% in wild-type mice), left ventricular size (length 0.82 +/- 0.04 vs. 0.66 +/- 0.03 cm in wild types), and atrial natriuretic peptide and brain natriuretic peptide expression (mRNA: 2819 and 495% of wild-type mice, respectively) indicated hypertrophy. G alpha(i3) was significantly up-regulated in G alpha(i2) knockout mice (protein compared with wild type: 340 +/- 90% in G alpha(-/-)(i2) and 394 +/- 80% in beta(1)-tg/G alpha(-/-)(i2), respectively). G alpha(i2) deficiency combined with cardiac beta(1)-adrenoceptor overexpression strongly impaired survival and cardiac function. At 300 days of age, beta(1)-adrenoceptor overexpression alone had not induced cardiac hypertrophy or dysfunction while there was overt cardiomyopathy in mice additionally lacking G alpha(i2). We propose an enhanced effect of increased beta(1)-adrenergic drive by the lack of protection via G alpha(i2). G alpha(i3) up-regulation was not sufficient to compensate for G alpha(i2) deficiency, suggesting an isoform-specific or a concentration-dependent mechanism.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Keller, Kirsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Maass, Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED Dizayee, Sara UNSPECIFIED UNSPECIFIED UNSPECIFIED Leiss, Veronika UNSPECIFIED UNSPECIFIED UNSPECIFIED Annala, Suvi UNSPECIFIED UNSPECIFIED UNSPECIFIED Koeth, Jessica UNSPECIFIED UNSPECIFIED UNSPECIFIED Seemann, Wiebke K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller-Ehmsen, Jochen UNSPECIFIED UNSPECIFIED UNSPECIFIED Mohr, Klaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Nurnberg, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Engelhardt, Stefan UNSPECIFIED orcid.org/0000-0001-5378-8661 UNSPECIFIED Herzig, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Birnbaumer, Lutz UNSPECIFIED UNSPECIFIED UNSPECIFIED Matthes, Jan UNSPECIFIED orcid.org/0000-0003-2754-1555 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-385231
DOI:	10.1093/cvr/cvv235
Journal or Publication Title:	Cardiovasc. Res.
Volume:	108
Number:	3
Page Range:	S. 348 - 357
Date:	2015
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1755-3245
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SYMPATHETIC-NERVOUS-SYSTEM; HEART-FAILURE; BETA(2)-ADRENERGIC RECEPTOR; G-PROTEINS; GENE KNOCKOUT; MOUSE HEARTS; TROPONIN-I; HYPERTROPHY; INHIBITION; EXPRESSION Multiple languages Cardiac & Cardiovascular Systems Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/38523