Differences in cardiac calcium release channel (ryanodine receptor) expression in myocardium from patients with end-stage heart failure caused by ischemic versus dilated cardiomyopathy.

Abstract

The molecular basis for the systolic and diastolic dysfunction characteristic of end-stage heart failure in humans remains poorly understood. It has been proposed that both abnormal calcium handling and defects in the contractile apparatus may contribute to the myocardial dysfunction. Two channels, the calcium release channel (CRC) or ryanodine receptor of the sarcoplasmic reticulum (SR), and the slow calcium channel or dihydropyridine receptor (DHPR) of the transverse tubule, play key roles in regulating intracellular calcium concentration and in excitation-contraction (E-C) coupling in the heart. The DHPR serves as the voltage sensor and plasma membrane calcium channel resulting in activation of the CRC during E-C coupling in heart muscle. In this study, we investigated the levels of CRC expression in several forms of end-stage heart failure in humans. A cardiac CRC cDNA was cloned from rabbit and used as a probe for Northern blot analyses to determine mRNA levels in the left ventricles of normal (n=4) and cardiomyopathic (n=34) human hearts from patients undergoing cardiac transplantation. Compared with normal patients, patients with ischemic cardiomyopathy (n=18) showed a 28% decrease in CRC mRNA levels (p<0.025) and patients with idiopathic dilated cardiomyopathy (n=14) a nonsignificant 12% increase. In these same hearts, a-actin levels were unchanged in end-stage heart failure, as has been previously reported. This is the first report indicating that the expression of the CRC mRNA is abnormal in end-stage human heart failure. The decreased expression of the CRC found specifically in patients with ischemic myopathy (but not idiopathic dilated cardiomyopathy) may, in part, explain differences in calcium handling and response to therapy observed among patients with different forms of cardiomyopathy. Decreased CRC expression could be related to abnormal contractile function in cardiomyopathic muscle resulting from ischemic insult. (Circulation Research 1992;71:18-26) KEY WoRDs * idiopathic dilated cardiomyopathy channel * mRNA * ryanodine receptor T Nhe calcium release channel (CRC) or ryanodine receptor of the sarcoplasmic reticulum (SR) is a large (565-kd) protein that forms the foot structure associating the SR with the transverse tubule

Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia

“…25 RyR2 is downregulated in experimental heart failure in dogs, 25,26 and the RyR2 protein and mRNA levels are also subnormal in failing human myocardium. 27 Our data suggest that FPVT is a disease showing close kinship to malignant hyperthermia and central core disease, which are rare, dominantly inherited disorders of calcium signaling in striated muscle resulting from mutations of the RyR1 gene. 28,29 Malignant hyperthermia is characterized by skeletal muscle rigidity and contractures, malignant cardiac arrhythmias, hypermetabolism, and eventually fever, which is typically triggered by the administration of halothane or depolarizing skeletal muscle relaxants.…”

A Mechanistic Analysis of Reduced Mechanical Performance in Human Heart Failure

“…13,15,[19][20][21][22][23] Along with this depression in SERCA 2 pump protein it was shown that in failing hearts, where the severity of failure was assessed by ventricular ANF mRNA levels, there is a correlation among SERCA2 calcium pump ATPase, phospholamban as well as ryanodine receptor mRNA (Figure 8). 11) Thus it would appear that in failing hearts all of the sarcoplasmic reticular calcium cycling proteins are down regulated and this observation has been supported by a number of additional measurements 21,24,25) (Figure 9). In contrast to the down regulation of the calcium cycling proteins in the sarcoplasmic reticulum, there is an up regulation of the sarcolemmal sodiumcalcium exchange protein where the mRNA level normalized for 18S mRNA and the protein normalized per myosin heavy chain is increased by 83 % (p < 0.05) and 85 % (p < 0.05), respectively 17) (Figure 9).…”

Cellular Distribution of Ca 2+ Pumps and Ca 2+ Release Channels in Rat Cardiac Hypertrophy Induced by Aortic Stenosis

“…16,30 In failing human hearts, RyR2 mRNA level is decreased in various types of cardiopathies 31 but unchanged in dilated cardiopathy. 32 Decrease in ryanodine receptor mRNA level is correlated with decreased SERCA 2 and phospholamban mRNA levels, suggesting that these genes are coordinately regulated and that they are inversely correlated to the level of ANF 20 and IP 3 R mRNAs. 31 In contrast, RyR2 protein level and the number of high-affinity Ryanocline binding sites were similar in nonfailing and failing human hearts.…”

“…31 In contrast, RyR2 protein level and the number of high-affinity Ryanocline binding sites were similar in nonfailing and failing human hearts. 32 Thus, as for SERCA 2, data concerning the expression of RyR2 in human cardiopathy are conflicting. In animal models, however, severe compensated hypertrophy is generally associated with a decrease in the expression of SERCA 2 and RyR2.…”