Cardiac remodeling in Gα_q and Gα₁₁ knockout mice

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• 作者：Kathrina Wiesen^a ; ^b ; Elisabeth Kaiser^b ; Laura Schrö ; der^b ; Anke Scholz^b ; Sandra Ruppenthal^b ; Jan-Christian Reil^c ; Christina Backes^d ; Eckart Meese^d ; Carola Meier^e ; Anna Bogdanova^a ; Peter Lipp^b ; ¹ ; ^{peter.lipp@uks.eu" class="auth_mail" title="E-mail the corresponding author} ; Lars Kaestner^b ; ¹ ; ^{lars_kaestner@me.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Gαq/Gα11-signaling ; Cardiac tissue-remodeling ; Matricellular proteins ; Cyr61
• 刊名：International Journal of Cardiology
• 出版年：2016
• 出版时间：1 January 2016
• 年：2016
• 卷：202
• 期：Complete
• 页码：836-845
• 全文大小：1420 K

文摘

Although both Gα_q- and Gα₁₁-protein signaling are believed to be involved in the regulation of cardiac hypertrophy, their detailed contribution to myocardial function remains elusive.

Methods and results

We studied remodeling processes in healthy transgenic mice with genetically altered Gα_q/Gα₁₁-expression, in particular a global Gα₁₁-knockout and a novel inducible cardiac specific Gα_q-knockout, as well as a combined double knockout (dKO) mouse line. Echocardiography and telemetric ECG recordings revealed that compared with wild type mice, hearts of dKO mice showed an increased ejection fraction and a decreased heart rate, irrespective of age resulting in a maintained cardiac output. We attributed these findings to the lack of Gα_11, which the absence was associated with a decreased afterload. Histological analysis of the extracellular matrix in the heart depicted a diminished presence of collagen in aging hearts of dKO mice compared to wild-type mice. The results of a transcriptome analysis on isolated ventricular cardiac myocytes revealed alterations of the activity of genes involved in the Gα_q/Gα₁₁-dependent regulation of the extracellular matrix, such as the matricellular protein Cyr61.

Conclusions

From our data we conclude that Gα_q/Gα₁₁ signaling pathways play a pivotal role in maintaining gene activity patterns. For the heart we revealed their importance in modulating the properties of the extracellular matrix, a mechanism that might be an important contributor and mechanistic basis for the development of pressure-overload induced cardiac hypertrophy.