MULTIDRUG RESISTANCE PROTEIN 5 (MRP5), A CGMP EFFLUX TRANSPORTER IS UPREGULATED IN LEFT VENTRICULAR MYOCARDIUM OF DOGS WITH CHRONIC HEART FAILURE
Gupta RC, Singh-Gupta V, and Sabbah HN. MULTIDRUG RESISTANCE PROTEIN 5 (MRP5), A CGMP EFFLUX TRANSPORTER IS UPREGULATED IN LEFT VENTRICULAR MYOCARDIUM OF DOGS WITH CHRONIC HEART FAILURE. J Am Coll Cardiol 2019; 73(9):755.
J Am Coll Cardiol
Background: Cyclic guanosine monophosphate (cGMP) signaling plays a pivotal role in modulating vascular tone, cardiac contractility and renal function. cGMP signaling include cGMP-generating guanylyl-cyclases, protein kinases, phosphodiesterases, efflux transporters or cGMP exporters and hence substances that increase cGMP levels are important targets for the treatment of heart failure (HF). cGMP exporters pump cGMP out of the cell and, in addition to metabolic cGMP degradation by phosphodiesterases, may contribute to the observed reduction of cGMP in cardiomyocytes of failing human and dog heart. This study tested the hypothesis that the sarcolemmal cGMP exporter multidrug resistance protein 5 (MRP5) is upregulated in LV myocardium HF and hence contributes to reduced cytosolic levels of cGMP. Methods: Studies were performed in LV tissue of 7 dogs with HF produced by coronary microembolizations (EF≤35%) and 7 normal (NL) dogs. Protein levels of MRP5 and annexin-VI (ANX-VI), a sarcolemmal L-type Ca2+ channel modulating protein used as an internal loading control, were determined in isolated LV sarcolemmal fractions using specific antibodies and Western blotting. Bands were quantified in densitometric units (du). mRNA levels of MRP5 and GAPDH, as internal control, were determined in LV homogenate using specific primers and real-time PCR. Results: ANX-VI protein and GAPDH mRNA levels were unchanged between NL and HF dogs. MRP5 mRNA levels normalized to GAPDH was ∼4.9 folds higher in LV of HF dogs compared to NL dogs. Furthermore, compared to NL dogs, MRP5 protein levels normalized to ANXVI was also significantly higher in HF dogs compared to NL dogs (1.15 ± 0.07 vs. 0.38 ± 0.05 du, p<0.05). Conclusion: MRP5 protein and mRNA levels are significantly upregulated in LV myocardium of dogs with chronic HF. Excessive cGMP export out of the cell can partly account for low levels of cGMP in the failing heart. Therapy that targets MRP5 inhibition can potentially serve to increase cytosolic cGMP levels and serve to improve cardiomyocyte function in HF.
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