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Selective regulation of cardiac organic cation transporter novel type 2 (OCTN2) in dilated cardiomyopathy

Markus Grube1, Sabine Ameling, Michel Noutsias

  • 1Department of Pharmacology, Ernst-Moritz-Arndt University, Greifswald, Germany.

The American Journal of Pathology
|June 7, 2011
PubMed

Insights

Organic cation transporters (OCTs and OCTNs) are present in the heart and interact with cardiovascular drugs. OCTN2 transporter expression is reduced in dilated cardiomyopathy, predicting impaired cardiac function.

Area of Science:

  • Cardiovascular Biology
  • Molecular Pharmacology
  • Medical Biochemistry

Background:

  • Organic cation transporters (OCTs and OCTNs) are crucial for cellular uptake of endogenous compounds and drugs.
  • Genetic variations in OCTN2 are linked to carnitine deficiency and heart failure.
  • The impact of disease on cardiac OCT and OCTN expression and function remains largely unexplored.

Purpose of the Study:

  • To investigate the cardiac expression, regulation by heart failure, and drug interactions of OCTs and OCTNs.
  • To determine the role of these transporters in dilated cardiomyopathy.
  • To assess the correlation between OCTN2 expression and cardiac function.

Main Methods:

  • Quantitative real-time PCR and Western blotting to assess transporter mRNA and protein levels in human heart samples and a mouse model.
  • Functional assays to determine drug interactions and inhibition kinetics (IC50 values).
  • Analysis of endomyocardial biopsy specimens from patients with dilated cardiomyopathy and healthy controls.

Main Results:

  • Cardiac mRNA expression levels were ranked OCTN2 > OCT3 > OCTN1 > OCT1; OCT2 was undetectable.
  • Proteins localized to vascular structures (OCT3, OCTN2, OCTN1) and cardiomyocytes (OCT1, OCTN1).
  • OCT1 showed significant inhibition by cardiovascular drugs like carvedilol, diltiazem, and propafenone.
  • Coxsackievirus-induced cardiomyopathy in mice led to a significant reduction in Octn2 mRNA expression.
  • OCTN2 expression was significantly decreased in dilated cardiomyopathy patients and correlated with reduced left ventricular ejection fraction and increased cardiac T cells.

Conclusions:

  • OCT1, OCT3, OCTN1, and OCTN2 are expressed in the human heart and interact with cardiovascular drugs.
  • OCTN2 expression is selectively downregulated in dilated cardiomyopathy.
  • Reduced OCTN2 expression in the heart is associated with impaired cardiac function and may serve as a predictive biomarker.

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