Endothelin-1 critically influences cardiac function, as even a modest (~35%) decrease in Edn1 expression is sufficient to cause dilated cardiomyopathy via a superoxide-Mmp9 cascade.
Does endothelin-1 expression level influence cardiac function via the superoxide-MMP9 cascade in mice?
Endothelin-1 is critical for maintaining normal contractile function and preventing overstretching via regulation of the superoxide-MMP9 cascade.
We have generated low-expressing and high-expressing endothelin-1 genes (L and H) and have bred mice with four levels of expression: L/L, ∼20%; L/+, ∼65%; +/+ (wild type), 100%; and H/+, ∼350%. The hypomorphic L allele can be spatiotemporally switched to the hypermorphic H allele by Cre-loxP recombination. Young adult L/L and L/+ mice have dilated cardiomyopathy, hypertension, and increased plasma volumes, together with increased ventricular superoxide levels, increased matrix metalloproteinase 9 (Mmp9) expression, and reduced ventricular stiffness. H/+ mice have decreased plasma volumes and significantly heavy stiff hearts. Global or cardiomyocyte-specific switching expression from L to H normalized the abnormalities already present in young adult L/L mice. An epithelial sodium channel antagonist normalized plasma volume and blood pressure, but only partially corrected the cardiomyopathy. A superoxide dismutase mimetic made superoxide levels subnormal, reduced Mmp9 overexpression, and substantially improved cardiac function. Genetic absence of Mmp9 also improved cardiac function, but increased superoxide remained. We conclude that endothelin-1 is critical for maintaining normal contractile function, for controlling superoxide and Mmp9 levels, and for ensuring that the myocardium has sufficient collagen to prevent overstretching. Even a modest (∼35%) decrease in endothelin-1 gene (Edn1) expression is sufficient to cause cardiac dysfunction.
Hathaway et al. (Mon,) conducted a other in Dilated cardiomyopathy and cardiac dysfunction. Genetic modification of endothelin-1 expression, epithelial sodium channel antagonist, superoxide dismutase mimetic, and Mmp9 deletion vs. Wild type (+/+) or baseline L/L mice was evaluated on Cardiac function, superoxide levels, Mmp9 expression, plasma volume, and blood pressure. Endothelin-1 critically influences cardiac function, as even a modest (~35%) decrease in Edn1 expression is sufficient to cause dilated cardiomyopathy via a superoxide-Mmp9 cascade.
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