Proximal spinal muscular atrophy (SMA) is a debilitating neurological disease marked by isolated lower motor neuron death and subsequent atrophy of skeletal muscle. Historically, SMA pathology was thought to be limited to lower motor neurons and the skeletal muscles they control, yet there are several reports describing the coincidence of cardiovascular abnormalities in SMA patients. As new therapies for SMA emerge, it is necessary to determine whether these non-neuromuscular systems need to be targeted. Therefore, we have characterized left ventricular (LV) function of SMA mice (SMN2+/+; SMNΔ7+/+; Smn-/-) and compared it with that of their unaffected littermates at 7 and 14 days of age. Anatomical and physiological measurements made by electrocardiogram and echocardiography show that affected mouse pups have a dramatic decrease in cardiac function. At 14 days of age, SMA mice have bradycardia and develop a marked dilated cardiomyopathy with a concomitant decrease in contractility. Signs of decreased cardiac function are also apparent as early as 7 days of age in SMA animals. Delivery of a survival motor neuron-1 transgene using a self-complementary adeno-associated virus serotype 9 abolished the symptom of bradycardia and significantly decreased the severity of the heart defect. We conclude that severe SMA animals have compromised cardiac function resulting at least partially from early bradycardia, which is likely attributable to aberrant autonomic signaling. Further cardiographic studies of human SMA patients are needed to clarify the clinical relevance of these findings from this SMA mouse.
Immediately after ACF induction, eccentric LV remodeling is mediated by interstitial collagen loss without cardiomyocyte elongation. Acute BK2R blockade prevents eccentric LV remodeling and improves function. Chronic ACE inhibition does not prevent eccentric LV remodeling or improve function. These findings suggest that ACE inhibitor-mediated increase in LV BK exacerbates matrix loss and explains why ACE inhibition is ineffective in VO.
The mature aortic valve is composed of a structured trilaminar extracellular matrix that is interspersed with aortic valve interstitial cells (AVICs) and covered by endothelium. Dysfunction of the valvular endothelium initiates calcification of neighboring AVICs leading to calcific aortic valve disease (CAVD). The molecular mechanism by which endothelial cells communicate with AVICs and cause disease is not well understood. Using a co-culture assay, we show that endothelial cells secrete a signal to inhibit calcification of AVICs. Gain or loss of nitric oxide (NO) prevents or accelerates calcification of AVICs, respectively, suggesting that the endothelial cell-derived signal is NO. Overexpression of Notch1, which is genetically linked to human CAVD, retards the calcification of AVICs that occurs with NO inhibition. In AVICs, NO regulates the expression of Hey1, a downstream target of Notch1, and alters nuclear localization of Notch1 intracellular domain. Finally, Notch1 and NOS3 (endothelial NO synthase) display an in vivo genetic interaction critical for proper valve morphogenesis and the development of aortic valve disease. Our data suggests that endothelial cell-derived NO is a regulator of Notch1 signaling in AVICs in the development of the aortic valve and adult aortic valve disease.
([Ca 2ϩ ] i ) in cardiomyocytes and to have positive inotropic effects on the heart (1, 2). In addition to their importance in the acute regulation of cardiac function, their significance has increased further as the transcriptional pathways that lead to cardiac hypertrophy have been elucidated. Although initially compensatory, prolonged hypertrophy is often associated with decompensation, dilated cardiomyopathy, arrhythmia, fibrotic disease, and heart failure (3).The importance of agonists that activate PLC to cardiac hypertrophy is now well established (4). One well studied mouse model of cardiac hypertrophy involves the overexpression of a constitutively active form of a G protein subunit, G␣ q , which leads to chronic activation of PLC and the continuous production of IP 3 and diacylglycerol (5). In addition, overexpression in the heart of the PLC-activating angiotensin II (Ang II) type I receptor also leads to hypertrophy (6, 7). More clinically relevant, hypertrophied hearts induced by volume overload are commonly characterized by high levels of IP 3 -generating agonists such as Ang II (8).There are multiple signaling pathways downstream of PLC leading to cardiac hypertrophy. One involves diacylglycerol, protein kinase C, small guanine nucleotide-binding proteins (9), the MEK1-ERK1/2 branch of the mitogen-activated protein kinase pathway (10), and the transcription factor GATA4 (11, 12). Two others involve IP 3 and elevated levels of [Ca 2ϩ ] i . One of these is dependent on Ca 2ϩ /calmodulin-dependent calmodulin kinase and the transcription factor MEF2 (13), and the other is mediated by the Ca 2ϩ /calmodulin-activated protein phosphatase calcineurin and the transcription factor NFAT3 (14). The latter signaling pathway was first defined in lymphocytes (15) and is fundamental to an array of biological responses in a variety of cell types (16,17). A rise in [Ca 2ϩ ] i triggered by ligands generating IP 3 leads to the activation of the phosphatase activity of calcineurin, the dephosphorylation of NFAT family members, and their translocation to the nucleus to initiate transcription. Rapid export of NFAT from the nucleus when [Ca 2ϩ ] i levels drop prevents brief [Ca 2ϩ ] i pulses from initiating transcription of NFATdependent genes (15,16).A critical, unresolved issue for cardiac hypertrophy is the mechanism leading from IP 3 -mediated stimuli to elevated [Ca 2ϩ ] i . In most cell types, the initial increase in [Ca 2ϩ ] i in response to IP 3 -generating agonists is due to the release of Ca 2ϩ from the endoplasmic reticulum (ER
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