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Calcium and Cardiovascular Diseases: A Series of Twelve Articles in Advanced Cardiology

Curator: Aviva Lev-Ari, PhD, RN

UPDATED on 7/18/2021

IMAGE SOURCE:

Claudio A. Hetz. Antioxidants & Redox Signaling.Dec 2007.

2345-2356. http://doi.org/10.1089/ars.2007.1793

FIG. 3. Regulation of ER calcium homeostasis by the BCL-2 protein family. Different anti- and proapoptotic members of the BCL-2 family of proteins are located at the ER membrane, where they have an important role regulating ER calcium content. BCL-2 and BCL-XL interact with the IP3R calcium channel, modulating its activity. BCL-2 has been shown to increase ER calcium leak through the IP3R because of an increase on its phosphorylation levels.

BAX and BAK have the opposite effect on ER calcium content, a function that may be further modulated by BH3-only proteins (such as PUMA and BIK). In addition, the activity of BCL-2 at the ER membrane is regulated by phosphorylation. JNK phosphorylates BCL-2, decreasing its antiapoptotic activity and increasing ER calcium content, whereas the phosphatase PP2A decreases this phosphorylation through a direct interaction. Alternatively, ER stress activates the IRE1/JNK pathway that may alter the activity of BCL-2 at the ER membrane. BI-1 is also located at the ER membrane, where it regulates calcium homeostasis.

CONCLUSIONS AND THERAPEUTIC PERSPECTIVES

I have summarized different pieces of evidence suggesting that the BCL-2 family of proteins has evolved to regulate multiple processes involved in cell survival under stress conditions. The global view of the current state of the field indicates that the BCL-2–related proteins are not only the “death gateway” keeper (as upstream regulators of caspases), but they also have multiple functions in essential processes for the cell. BCL-2–related proteins are particularly important in the physiologic maintenance of the ER, where they operate as

(a) a calcium rheostat,

(b) modulators of the UPR,

(c) regulators of ER network structure, and

(d) regulators of autophagy.

In addition, examples of a role of the BCL-2 family of proteins in cell-cycle regulation (87, 113), DNA damage responses (37, 114), and glucose/energy metabolism (16) are available, strongly supporting the notion that the BCL-2 protein family is a multifunctional group of proteins that, under normal conditions, participate in essential cellular process. In doing so, the BCL-2 protein family may represent specialized stress sentinels that actively participate in essential processes, allowing a constant homeostatic “quality control.” In response to irreversible cellular damage, particular BCL-2 family members may turn into direct activators of apoptosis.

Mutations in specific genes are responsible for a variety of neurologic disorders due to the misfolding and accumulation of abnormal protein aggregates in the brain. In many of these diseases, it has been suggested that alteration in the homeostasis of the ER contributes significantly to neuronal dysfunction.

These diseases include Parkinson’s disease (32, 84), Alzheimer’s disease (22), prion diseases (27, 28, 31), amyotrophic lateral sclerosis (ALS) (97), Huntington’s disease (63, 90) and many others (see list of diseases in 86). Consequently, the first steps in the death pathways downstream of ER stress represent important therapeutic targets. In this line of thinking, pharmacologic manipulation of the activity of the BCL-2 protein family may have beneficial consequences to treat these fatal diseases. Different small molecules and synthetic peptides are currently available with proven therapeutic applications in mouse disease models, including BCL-2 inhibitors (71), BAX channel inhibitors (29), BAX/BAK activator peptides (100, 101) and many others (see reviews in 52, 79). These drugs may be used as pharmacologic tools to manipulate the activity of stress-signaling pathways regulated by the BCL-2 protein family (i.e., autophagy, calcium metabolism, or the UPR) and their possible role in pathologic conditions.

SOURCE

Claudio A. Hetz.Antioxidants & Redox Signaling.Dec 2007.

2345-2356. http://doi.org/10.1089/ars.2007.1793

• Published in Volume: 9 Issue 12: November 2, 2007
• Online Ahead of Print: September 13, 2007

UPDATED on 7/1/2015

We add the following to this series:

Part XIII 

Ca2+-Stimulated Exocytosis:  The Role of Calmodulin and Protein Kinase C in Ca2+ Regulation of Hormone and Neurotransmitter
Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part I:

Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

Part II:

Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN

Part III:

Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H. Bernstein, MD, FCAP, Stephen J. Williams, PhD
 and Aviva Lev-Ari, PhD, RN

Part IV:

The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, ArterialSmooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

Part V:

Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

Larry H Bernstein, MD, FCAP, Justin Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

Part VI:

Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

Part VII:

Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part VIII

Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism – Part VIII

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part IX

Calcium-Channel Blockers, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor – Part IX

Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part X

Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission – Part X

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part XI

Sensors and Signaling in Oxidative Stress – Part XI

Larry H. Bernstein, MD, FCAP

Part XII

Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD)) – Part XII

Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD,