The calcium release-activated calcium channel Orai1 represents a crucial component in hypertrophic compensation and the development of dilated cardiomyopathy.

As exceptionally calcium selective store-operated channels, Orai channels play a prominent role in cellular calcium signaling. While most studied in the immune system, we are beginning to recognize that Orai1 provides unique calcium signaling pathways in numerous tissue contexts. To assess the involvement of Orai1 in cardiac hypertrophy we used transverse aortic constriction to model pressure overload cardiac hypertrophy and heart failure in Orai1 deficient mice. We demonstrate that Orai1 deficient mice have significantly decreased survival in this pressure overload model. Transthoracic echocardiography reveals that Orai1 deficient mice develop rapid dilated cardiomyopathy, with greater loss of function, and histological and molecular data indicate that this pathology is associated with significant apoptosis, but not major differences in cellular hypertrophy, fibrosis, and some major hypertrophic makers. Orai1 represents a crucial calcium entry mechanism in the compensation of the heart to pressure overload over-load, and the development of dilated cardiomyopathy.

Case of cephalothoracopagus conjoined twinning in an embryonic mouse.

BACKGROUND: Cephalothoracopagus twinning is extremely rare, and it is characterized by fusion of the head and thorax, two separate spines, pelves, and fore- and hindlimbs. CASE: In this case study, we describe cephalothoracopagus twinning in an embryonic mouse displaying a large but exencephalic head, median facial cleft, a single eye, and a second hindbrain rotated roughly 90° from a second spinal cord. There is a bony connection joining the clavicles, resulting in merged asternal thoracic cavities containing two hearts and four lungs. The abdominal cavities contain double caudal digestive tract structures, but a single esophagus and stomach. CONCLUSION: There are several proposed theories regarding the mechanism of spontaneous conjoined twinning; however, the specific mechanisms are still largely unknown. In this report, we highlight the morphological features in a murine example of cephalothoracopagus twinning, furthering our understanding of this rare occurrence while also demonstrating developmental morphogenesis consistent with that reported for human conjoined twins.

Successful TRPV1 antagonist treatment for cardiac hypertrophy and heart failure in mice.

Heart failure is becoming a global epidemic. It exerts a staggering toll on quality of life, and substantial medical and economic impact. In a pre-clinical model of cardiac hypertrophy and heart failure, we were able to overcome loss of heart function by administering the TRPV1 antagonist BCTC (4-(3-Chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazinecarboxamide). The results presented here identify TRPV1 antagonists as new treatment options for cardiac hypertrophy and heart failure.

Corin-deficient W-sh mice poorly tolerate increased cardiac afterload.

C57BL/6-Kit(W-sh/W-sh) mice are generally regarded as a mast cell-deficient model, as they lack the necessary kit receptor for mast cell development. Further characterization of this strain, however, indicates that C57BL/6-Kit(W-sh/W-sh) mice also have a disruption in the Corin gene. Corin is a transmembrane serine protease critical for processing atrial natriuretic peptide (ANP) from pro-ANP through proteolytic cleavage. Pro-ANP is produced, stored and released by cardiac myocytes in response to atrial stretch and the stress generated by increased afterload such as increased ventricular pressure from aortic stenosis or myocardial infarction. ANP inhibits the effects of the renin-angiotensin system to preserve homeostasis under conditions of increased hemodynamic load, and changes in the level of its activating enzyme Corin have been observed during the progression to heart failure. Here, we investigate the effect of increased hemodynamic load on Corin-deficient C57BL/6-Kit(W-sh/W-sh) mice. Ten-week old male mice were subjected to transverse aortic constriction for 8 weeks and were monitored for changes in cardiac structure and function by echocardiography. Hearts were collected 8 weeks after surgery for molecular and histological analyses. Corin-deficient C57BL/6-Kit(W-sh/W-sh) mice developed rapidly progressive and substantial left ventricular dilation, hypertrophy, and markedly impaired cardiac function during the 8 weeks after surgery, compared to wildtype mice. Concomitant with this we observed increased levels of ANP transcript, but a lack of prepro-ANP or pro-ANP protein in heart tissue extracted from Corin-deficient mice. Surprisingly, fibrosis was not increased in Corin-deficient mice when compared to wildtype mice. These data indicate that Corin's involvement in ANP processing is a key element in the heart's response to increased hemodynamic load. Further, C57BL/6-Kit(W-sh/W-sh) strain is an effective model for investigating the involvement of Corin and, conversely, a less than optimal model for investigating mast cell, and immunological, functions in certain cardiovascular pathologies.

Mice lacking functional TRPV1 are protected from pressure overload cardiac hypertrophy.

TRPV1 (transient receptor potential cation channel, subfamily V, member 1) is best studied in peripheral sensory neurons as a pain receptor; however TRPV1 is expressed in numerous tissues and cell types including those of the cardiovascular system. TRPV1 expression is upregulated in the hypertrophic heart, and the channel is positioned to receive stimulatory signals in the hypertrophic heart. We hypothesized that TRPV1 has a role in regulating cardiac hypertrophy. Using transverse aortic constriction to model pressure overload cardiac hypertrophy we show that mice lacking functional TRPV1, compared to wild type, have improved heart function, and reduced hypertrophic, fibrotic and apoptotic markers. This suggests that TRPV1 plays a role in the progression of cardiac hypertrophy, and presents a possible therapeutic target for the treatment of cardiac hypertrophy and heart failure.