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CAP2 in cardiac conduction, sudden cardiac death and eye development.

Field J, Ye DZ, Shinde M, Liu F, Schillinger KJ, Lu M, Wang T, Skettini M, Xiong Y, Brice AK, Chung DC, Patel VV - Sci Rep (2015)

Bottom Line: One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics.To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes.We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.

ABSTRACT
Sudden cardiac death kills 180,000 to 450,000 Americans annually, predominantly males. A locus that confers a risk for sudden cardiac death, cardiac conduction disease, and a newly described developmental disorder (6p22 syndrome) is located at 6p22. One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics. To determine the role of CAP2 in vivo, we generated knockout (KO) mice. cap2(-)/cap2(-) males were underrepresented at weaning and ~70% died by 12 weeks of age, but cap2(-)/cap2(-) females survived at close to the expected levels and lived normal life spans. CAP2 knockouts resembled patients with 6p22 syndrome in that mice were smaller and they developed microphthalmia and cardiac disease. The cardiac disease included cardiac conduction disease (CCD) and, after six months of age, dilated cardiomyopathy (DCM), most noticeably in the males. To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes. We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias. These studies establish a direct role for CAP2 and actin dynamics in sudden cardiac death and cardiac conduction disease.

No MeSH data available.


Related in: MedlinePlus

DCM in older male mice.(a–f) Trichrome staining of adult hearts (a) 37 week old WT male (b) 51 week old cap2loxp/cap2loxp male ((c), 37 week old and (d), 69 week old) cap2−/cap2− males; (e) 72 week old cap2+/cap2− female (f) 54 week old cap2−/cap2− female; (g) ANP staining of WT male (h) ANP staining of the cap2−/cap2− male from panel d. Size bar 25 μΜ. Areas staining blue indicate fibrosis. (i) Expression of CARP in cap2−/cap2− and cardiomyocyte specific knockout mice.
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f4: DCM in older male mice.(a–f) Trichrome staining of adult hearts (a) 37 week old WT male (b) 51 week old cap2loxp/cap2loxp male ((c), 37 week old and (d), 69 week old) cap2−/cap2− males; (e) 72 week old cap2+/cap2− female (f) 54 week old cap2−/cap2− female; (g) ANP staining of WT male (h) ANP staining of the cap2−/cap2− male from panel d. Size bar 25 μΜ. Areas staining blue indicate fibrosis. (i) Expression of CARP in cap2−/cap2− and cardiomyocyte specific knockout mice.

Mentions: We centered our analysis on the hearts of cap2−/cap2− mice because the male cap2−/cap2− mice were prone to sudden death without any other noticeable signs of distress and CAP2 is highly expressed in heart muscle. When we analyzed the hearts from 7 cap2−/cap2− (3 males and 4 females), 2 cap2−/cap2+ and 6 cap2+/cap2+ mice by histology, trichrome staining revealed a modest increase in right and left ventricular chamber size with abundant interstitial fibrosis separating and replacing the cardiomyocytes throughout the myocardium of one cap2−/cap2− male (blue staining areas) and a more modest interstitial fibrosis in a second male. None of the 4 female cap2−/cap2− mice showed significant differences from controls (Fig. 4). The male in Fig. 4d, which had extensive myocardial fibrosis, also had increased ANP staining in the left ventricle, which has been linked to the severity of clinical heart failure in humans (Fig. 4g,h)36, although ANP was not detected in the other hearts (not shown). In addition, cardiac ankyrin repeat protein (CARP), a transcriptional regulator that is often up-regulated with heart failure, was also elevated, more often in mutant male than female mice. A strong signal was observed in three of 3 males, but only in one of 3 females (Fig. 4i).


CAP2 in cardiac conduction, sudden cardiac death and eye development.

Field J, Ye DZ, Shinde M, Liu F, Schillinger KJ, Lu M, Wang T, Skettini M, Xiong Y, Brice AK, Chung DC, Patel VV - Sci Rep (2015)

DCM in older male mice.(a–f) Trichrome staining of adult hearts (a) 37 week old WT male (b) 51 week old cap2loxp/cap2loxp male ((c), 37 week old and (d), 69 week old) cap2−/cap2− males; (e) 72 week old cap2+/cap2− female (f) 54 week old cap2−/cap2− female; (g) ANP staining of WT male (h) ANP staining of the cap2−/cap2− male from panel d. Size bar 25 μΜ. Areas staining blue indicate fibrosis. (i) Expression of CARP in cap2−/cap2− and cardiomyocyte specific knockout mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4663486&req=5

f4: DCM in older male mice.(a–f) Trichrome staining of adult hearts (a) 37 week old WT male (b) 51 week old cap2loxp/cap2loxp male ((c), 37 week old and (d), 69 week old) cap2−/cap2− males; (e) 72 week old cap2+/cap2− female (f) 54 week old cap2−/cap2− female; (g) ANP staining of WT male (h) ANP staining of the cap2−/cap2− male from panel d. Size bar 25 μΜ. Areas staining blue indicate fibrosis. (i) Expression of CARP in cap2−/cap2− and cardiomyocyte specific knockout mice.
Mentions: We centered our analysis on the hearts of cap2−/cap2− mice because the male cap2−/cap2− mice were prone to sudden death without any other noticeable signs of distress and CAP2 is highly expressed in heart muscle. When we analyzed the hearts from 7 cap2−/cap2− (3 males and 4 females), 2 cap2−/cap2+ and 6 cap2+/cap2+ mice by histology, trichrome staining revealed a modest increase in right and left ventricular chamber size with abundant interstitial fibrosis separating and replacing the cardiomyocytes throughout the myocardium of one cap2−/cap2− male (blue staining areas) and a more modest interstitial fibrosis in a second male. None of the 4 female cap2−/cap2− mice showed significant differences from controls (Fig. 4). The male in Fig. 4d, which had extensive myocardial fibrosis, also had increased ANP staining in the left ventricle, which has been linked to the severity of clinical heart failure in humans (Fig. 4g,h)36, although ANP was not detected in the other hearts (not shown). In addition, cardiac ankyrin repeat protein (CARP), a transcriptional regulator that is often up-regulated with heart failure, was also elevated, more often in mutant male than female mice. A strong signal was observed in three of 3 males, but only in one of 3 females (Fig. 4i).

Bottom Line: One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics.To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes.We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania 19041 USA.

ABSTRACT
Sudden cardiac death kills 180,000 to 450,000 Americans annually, predominantly males. A locus that confers a risk for sudden cardiac death, cardiac conduction disease, and a newly described developmental disorder (6p22 syndrome) is located at 6p22. One gene at 6p22 is CAP2, which encodes a cytoskeletal protein that regulates actin dynamics. To determine the role of CAP2 in vivo, we generated knockout (KO) mice. cap2(-)/cap2(-) males were underrepresented at weaning and ~70% died by 12 weeks of age, but cap2(-)/cap2(-) females survived at close to the expected levels and lived normal life spans. CAP2 knockouts resembled patients with 6p22 syndrome in that mice were smaller and they developed microphthalmia and cardiac disease. The cardiac disease included cardiac conduction disease (CCD) and, after six months of age, dilated cardiomyopathy (DCM), most noticeably in the males. To address the mechanisms underlying these phenotypes, we used Cre-mediated recombination to knock out CAP2 in cardiomyocytes. We found that the mice developed CCD, leading to sudden cardiac death from complete heart block, but no longer developed DCM or the other phenotypes, including sex bias. These studies establish a direct role for CAP2 and actin dynamics in sudden cardiac death and cardiac conduction disease.

No MeSH data available.


Related in: MedlinePlus