Key result
SLMAP-3 is downregulated in human dilated ventricles, and its overexpression promotes cardiomyocyte response to adrenergic stimuli by increasing intracellular calcium transients by almost 3-fold.
Why the study?
Because membrane proteins are implicated in dilated cardiomyopathy and heart failure, the authors evaluated sarcolemmal membrane-associated protein expression in dilated cardiomyopathy and its effect on cardiomyocyte contraction.
Does SLMAP-3 overexpression or knockdown alter cardiomyocyte contraction rate and response to adrenergic stimuli in preclinical models?
Does SLMAP-3 overexpression or knockdown alter cardiomyocyte contraction rate and response to adrenergic stimuli in preclinical models?
SLMAP-3 regulates cardiomyocyte contraction and adrenergic response, and its downregulation in dilated cardiomyopathy suggests it may be a novel biomarker and therapeutic target for heart failure.
May support SLMAP-3 as a target in heart failure models; leaves open clinical translation.
Structural dilation of cardiomyocytes (CMs) imposes a decline in cardiac performance that precipitates cardiac failure and sudden death. Since membrane proteins are implicated in dilated cardiomyopathy and heart failure, we evaluated the expression of the sarcolemmal membrane-associated protein (SLMAP) in dilated cardiomyopathy and its effect on CM contraction. We found that all 3 SLMAP isoforms (SLMAP-1, -2, and -3) are expressed in CMs and are downregulated in human dilated ventricles. Knockdown of SLMAPs in cultured CMs transduced with recombinant adeno-associated viral particles releasing SLMAP-shRNA precipitated reduced spontaneous contractile rate that was not fully recovered in SLMAP-depleted CMs challenged with isoproterenol (ISO), thus phenotypically mimicking heart failure performance. Interestingly, the overexpression of the SLMAP-3 full-length isoform induced a positive chronotropic effect in CMs that was more pronounced in response to ISO insult (vs. ISO-treated naïve CMs). Confocal live imaging showed that H9c2 cardiac myoblasts overexpressing SLMAP-3 exhibit a higher intracellular calcium transient peak when treated with ISO (vs. ISO-treated cells carrying a control adeno-associated viral particle). Proteomics revealed that SLMAP-3 interacts with the regulator of CM contraction, striatin. Collectively, our data demonstrate that SLMAP-3 is a novel regulator of CM contraction rate and their response to adrenergic stimuli. Loss of SLMAPs phenotypically mimics cardiac failure and crystallizes SLMAPs as predictive of dilated cardiomyopathy and heart failure.
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Nader et al. (2019) studied Dilated Cardiomyopathy. SLMAP-3 overexpression and knockdown vs. Control AAV or scrambled shRNA was evaluated on Cardiomyocyte spontaneous contraction rate and intracellular calcium transient peak. SLMAP-3 is downregulated in human dilated ventricles, and its overexpression promotes cardiomyocyte response to adrenergic stimuli by increasing intracellular calcium transients by almost 3-fold.
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