Myocardial hypertrophic remodeling and impaired left ventricular function in mice with a cardiac-specific deletion of Janus kinase 2

Xiaohong T. Gan, Venkatesh Rajapurohitam, Jenny Xue, Cathy Huang, Suresh Bairwa, Xilan Tang, Jeffrey T Y Chow, Melissa F W Liu, Felix Chiu, Kazuhito Sakamoto, Kay Uwe Wagner, Morris Karmazyn

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3 Scopus citations

Abstract

The Janus kinase (JAK) system is involved in numerous cell signaling processes and is highly expressed in cardiac tissue. The JAK isoform JAK2 is activated by numerous factors known to influence cardiac function and pathologic conditions. However, although abundant, the role of JAK2 in the regulation or maintenance of cardiac homeostasis remains poorly understood. Using the Cre-loxP system, we generated a cardiac-specific deletion of Jak2 in the mouse to assess the effect on cardiac function with animals followed up for a 4-month period after birth. These animals had marked mortality during this period, although at 4 months mortality in male mice (47%) was substantially higher compared with female mice (30%). Both male and female cardiac Jak2-deleted mice had hypertrophy, dilated cardiomyopathy, and severe left ventricular dysfunction, including a marked reduction in ejection fractions as assessed by serial echocardiography, although the responses in females were somewhat less severe. Defective cardiac function was associated with altered protein levels of sarcoplasmic reticulum calcium-regulatory proteins particularly in hearts from male mice that had depressed levels of SERCA2 and phosphorylated phospholamban. In contrast, SERCA2 was unchanged in hearts of female mice, whereas phosphorylated phospholamban was increased. Our findings suggest that cardiac JAK2 is critical for maintaining normal heart function, and its ablation produces a severe pathologic phenotype composed of myocardial remodeling, heart failure, and pronounced mortality.

Original languageEnglish (US)
Pages (from-to)3202-3210
Number of pages9
JournalAmerican Journal of Pathology
Volume185
Issue number12
DOIs
StatePublished - Dec 2015

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Gan, X. T., Rajapurohitam, V., Xue, J., Huang, C., Bairwa, S., Tang, X., Chow, J. T. Y., Liu, M. F. W., Chiu, F., Sakamoto, K., Wagner, K. U., & Karmazyn, M. (2015). Myocardial hypertrophic remodeling and impaired left ventricular function in mice with a cardiac-specific deletion of Janus kinase 2. American Journal of Pathology, 185(12), 3202-3210. https://doi.org/10.1016/j.ajpath.2015.08.007