Review

Sarco(endo)plasmic Reticulum Calcium Pumps in the Cardiovascular System: Function and Gene Expression

It is well known that cardiac dysfunction develops during sepsis in both humans and in rodents (rats, mice). These defects appear to be reversible, since after “recovery” from sepsis, cardiac dysfunction disappears and the heart returns to its function that was present before the onset of sepsis. Our studies, using in vivo and in vitro models, have demonstrated that C5a and its receptors (C5aR1 and C5aR2) play key roles in cardiac dysfunction developing during sepsis. Use of a neutralizing antibody to C5a largely attenuates cardiac dysfunction and other adverse events developing during sepsis. The molecular basis for cardiac dysfunctions is linked to generation of C5a and its interaction with C5a receptors present on surfaces of cardiomyocytes (CMs). It is established that C5a interactions with C5a receptors leads to significant reductions involving faulty contractility and relaxation in CMs. In addition, C5a interactions with C5a receptors on CMs results in reductions in Na⁺/K⁺-ATPase in CMs. This ATPase is essential for intact action potentials in CMs. The enzymatic activity and protein for this ATPase were strikingly reduced in CMs during sepsis by unknown mechanisms. In addition, C5a interactions with C5aRs also caused reductions in CM homeostatic proteins that regulate cytosolic [Ca²⁺]i in CMs: sarco/endoplasmic reticulum Ca²⁺-ATPase2 (SERCA2) and Na⁺/Ca²⁺ exchanger (NCX). In the absence of C5a receptors, defects in SERCA2 and NCX in CMs after sepsis are strikingly attenuated. These observations suggest new strategies to protect the heart from dysfunction developing during sepsis.

Calcium (Ca²⁺) recycling is key for effective relaxation of the cardiac muscle. Failure to properly recycle calcium through the sarcoplasmic reticulum (SR) results in severe impairment of myocardial relaxation and consequently alteration of the “beat-to-beat” heart rhythm and contractile function. The Sarco(Endo)plasmic reticulum Ca²⁺ ATPase (SERCA) is instrumental for recycling cytosolic Ca²⁺ into the lumen of the SR. Among the many SERCA isoforms identified so far, SERCA2a is restricted to slow-twitch skeletal and cardiac muscle, while SERCA2b is ubiquitously expressed. SERCA2a/b expression and activity are altered in major heart diseases such as ischemic heart disease, cardiomyopathies and congestive heart failure. Restoring adequate SERCA2a/b expression by pharmacological action or gene delivery has emerged as a new approach for the treatment of heart failure. In this review we describe the drugs adopted in clinical practice that activate SERCA2a/b function as well as new promising therapeutic tools using SERCA2 viral gene delivery to improve cardiac function and treat heart failure.

A variety of calcium signals can be produced by smooth muscle. Calcium signals in smooth muscles are associated with contraction and relaxation and the control of excitability. A major challenge to investigators is to elucidate which aspects of calcium signaling are physiologically relevant to particular smooth muscles, and what the functional consequences are of those calcium signals in health and disease. The challenge is to synthesize a cohesive account, while making some reference to aspects of specialization of mechanism found only in certain smooth muscles. This chapter focuses on calcium signals and contraction in tissues—uterus, ureter, and vascular—and discusses aspects of signaling in other smooth muscles. A paradigm shift in the role played by the SR in smooth muscle has occurred with the discovery that its most important role, at least in some tissues, is to control membrane excitability and act to dampen calcium influx and limit contraction.

Diastolic dysfunction is characterized by prolonged relaxation, increased filling pressure, decreased contraction velocity, and reduced cardiac output. Phenotypical features of diastolic dysfunction can be observed at the level of the isolated myocyte. This article reviews the cellular mechanisms that control relaxation at the level of the myocyte in the healthy situation and discusses the alterations that can affect physiologic function during disease. It focuses specifically on the mechanisms that regulate intracellular calcium handling, and the response of the myofilaments to calcium, including the changes in these components that can contribute to diastolic dysfunction.

Intracellular Ca²⁺ ([Ca²⁺]_i) may be a factor of importance to hypertension in spontaneously hypertensive rats (SHR). Platelet hyperactivity caused by increased [Ca²⁺]_i may contribute to atherothrombotic cardiovascular events. In a genome scan, we have recently demonstrated that a candidate quantitative trait locus (QTL) for [Ca²⁺]_i in platelets is located near the sarco(endo)plasmic reticulum Ca²⁺-dependent ATPase (Serca) II gene locus on chromosome 12 in backcrossed rats derived from SHR and normotensive Fischer 344 rats (F344).

Congenic substitution mapping was performed for the chromosomal region including the Serca II gene locus. The segment including the Serca II gene locus was transferred from F344 onto the genetic background of the progenitor SHR. Systolic blood pressure (SBP), platelet aggregation, and ratio of heart weight to body weight (HW/BW) as well as [Ca²⁺]_i responses in platelets were compared between SHR and the congenic strain.

Among the parental strains, thrombin-stimulated and thapsigargin-induced peak values of [Ca²⁺]_i in platelets, platelet aggregation, SBP, and HW/BW were significantly greater in SHR than in F344 and F₁ rats. The heterozygous congenic rats for the Serca II gene segment had significantly attenuated [Ca²⁺]_i responses and platelet aggregation compared with SHR. Furthermore, they demonstrated significantly lower SBP and HW/BW.

Congenic substitution mapping clarified that a chromosomal segment including the Serca II gene locus was responsible for attenuated [Ca²⁺]_i responses and platelet aggregation in the heterozygous congenic rats. Therefore, this chromosomal region may contribute to the development of hypertension and cardiac hypertrophy by augmenting Ca²⁺ signaling in SHR.