Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
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Query: UMLS:C0018799 (
heart disease
)
34,133
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Dilated cardiomyopathy (DCM) is the third most common cause of heart failure, with ~70% of DCM cases considered idiopathic. We showed recently, through genetic ablation of the
MGAT1
gene, which encodes an essential glycosyltransferase (GlcNAcT1), that prevention of cardiomyocyte hybrid/complex N-glycosylation was sufficient to cause DCM that led to heart failure and early death. Our findings are consistent with increasing evidence suggesting a link between aberrant glycosylation and heart diseases of acquired and congenital etiologies. However, the mechanisms by which changes in glycosylation contribute to disease onset and progression remain largely unknown. Activity and gating of voltage-gated Na
+
and K
+
channels (Na
v
and K
v
respectively) play pivotal roles in the initiation, shaping and conduction of cardiomyocyte action potentials (APs) and aberrant channel activity was shown to contribute to cardiac disease. We and others showed that glycosylation can impact Na
v
and K
v
function; therefore, here, we investigated the effects of reduced cardiomyocyte hybrid/complex N-glycosylation on channel activity to investigate whether chronic aberrant channel function can contribute to DCM. Ventricular cardiomyocytes from
MGAT1
deficient (MGAT1KO) mice display prolonged APs and pacing-induced aberrant early re-activation that can be attributed to, at least in part, a significant reduction in K
v
expression and activity that worsens over time suggesting
heart disease
-related remodeling. MGAT1KO Na
v
demonstrate no change in expression or maximal conductance but show depolarizing shifts in voltage-dependent gating. Together, the changes in MGAT1KO Na
v
and K
v
function likely contribute to observed anomalous electrocardiograms and Ca
2+
handling. These findings provide insight into mechanisms by which altered glycosylation contributes to DCM through changes in Na
v
and K
v
activity that impact conduction, Ca
2+
handling and contraction. The MGAT1KO can also serve as a useful model to study the effects of aberrant electrical signaling on cardiac function and the remodeling events that can occur with
heart disease
progression.
...
PMID:Reduced hybrid/complex N-glycosylation disrupts cardiac electrical signaling and calcium handling in a model of dilated cardiomyopathy. 3107 33
