Modulation of CaV1.2 Channel Function by Interacting Proteins and Post-Translational Modifications: Implications in Cardiovascular Diseases and COVID-19.

CaV1.2 calcium channel is the primary conduit for Ca2+ influx into cardiac and smooth muscles that underscores its importance in the pathogenesis of hypertension, atherosclerosis, myocardial infarction, and heart failure. But, a few controversies still remain. Therefore, exploring new ways to modulate CaV1.2 channel activity will augment the arsenal of CaV1.2 channel-based therapeutics for treatment of cardiovascular diseases. Here, we will mainly introduce a couple of emerging CaV1.2 channel interacting proteins, such as Galectin-1 and Cereblon, and discuss their roles in hypertension and heart failure through fine-tuning CaV1.2 channel activity. Of current interest, we will also evaluate the implication of the role of CaV1.2 channel in SARS-CoV-2 infection and the potential treatments of COVID-19-related cardiovascular symptoms.

Calcium Channel Splice Variants and Their Effects in Brain and Cardiovascular Function.

Calcium ions serve as an important intracellular messenger in many diverse pathways, ranging from excitation coupling in muscles to neurotransmitter release in neurons. Physiologically, the concentration of free intracellular Ca2+ is up to 10,000 times less than that of the extracellular concentration, and increases of 10- to 100-fold in intracellular Ca2+ are observed during signaling events. Voltage-gated calcium channels (VGCCs) located on the plasma membrane serve as one of the main ways in which Ca2+ is able to enter the cell. Given that Ca2+ functions as a ubiquitous intracellular messenger, it is imperative that VGCCs are under tight regulation to ensure that intracellular Ca2+ concentration remains within the physiological range. In this chapter, we explore VGCCs' inherent control of Ca2+ entry as well as the effects of alternative splicing in CaV2.1 and posttranslational modifications of CaV1.2/CaV1.3 such as phosphorylation and ubiquitination. Deviation from this physiological range will result in deleterious effects known as calcium channelopathies, some of which will be explored in this chapter.

Regulation of cardiovascular calcium channel activity by post-translational modifications or interacting proteins.

Voltage-gated calcium channels are the major pathway for Ca2+ influx to initiate the contraction of smooth and cardiac muscles. Alterations of calcium channel function have been implicated in multiple cardiovascular diseases, such as hypertension, atrial fibrillation, and long QT syndrome. Post-translational modifications do expand cardiovascular calcium channel structure and function to affect processes such as channel trafficking or polyubiquitination by two E3 ubiquitin ligases, Ret finger protein 2 (Rfp2) or murine double minute 2 protein (Mdm2). Additionally, biophysical property such as Ca2+-dependent inactivation (CDI) could be altered through binding of calmodulin, or channel activity could be modulated via S-nitrosylation by nitric oxide and phosphorylation by protein kinases or by interacting protein partners, such as galectin-1 and Rem. Understanding how cardiovascular calcium channel function is post-translationally remodeled under distinctive disease conditions will provide better information about calcium channel-related disease mechanisms and improve the development of more selective therapeutic agents for cardiovascular diseases.

Relationship between severity of obstructive sleep apnea and adverse cardiac outcomes in non-diabetic patients presenting with myocardial infarction.

Previous studies that have reported an association between obstructive sleep apnea and adverse cardiac events were confounded by a high prevalence of diabetes mellitus. We investigated the relationship between obstructive sleep apnea and the occurrence of major adverse cardiac events in non-diabetic patients who presented with ST-segment elevation myocardial infarction. A total of 41 patients who underwent overnight sleep screening within 5 days after admission for myocardial infarction from January 2007 to December 2008 were identified. Major adverse cardiac events-defined as a composite of cardiac death, non-fatal myocardial infarction, hospitalization for angina and congestive heart failure at 5-year follow-up-were determined. The patients were divided into two groups: those who experienced major adverse cardiac events and those who did not. In the overall cohort, the prevalence of obesity was 4.9 %. A total of 13 (31.7 %) patients had major adverse cardiac events. The mean apnea-hypopnea index was 25.4 ± 20.3. The group that experienced major adverse cardiac events had a higher apnea-hypopnea index than the group that did not (36.1 ± 21.0 vs 20.4 ± 18.2; P = 0.016). After adjusting for the resolution of ST-segment elevation and the use of a glycoprotein IIb/IIIa inhibitor, logistic regression analysis revealed that the apnea-hypopnea index remained an independent predictor of major adverse cardiac events (odds ratio 1.044; 95 % confidence interval 1.003-1.086; P = 0.033). In non-diabetic patients, the severity of obstructive sleep apnea was associated with the occurrence of major adverse cardiac events at 5-year follow-up after ST-segment elevation myocardial infarction.

Elevated brain temperature under severe heat exposure impairs cortical motor activity and executive function.

BACKGROUND: Excessive heat exposure can lead to hyperthermia in humans, which impairs physical performance and disrupts cognitive function. While heat is a known physiological stressor, it is unclear how severe heat stress affects brain physiology and function. METHODS: Eleven healthy participants were subjected to heat stress from prolonged exercise or warm water immersion until their rectal temperatures (Tre) attained 39.5°C, inducing exertional or passive hyperthermia, respectively. In a separate trial, blended ice was ingested before and during exercise as a cooling strategy. Data were compared to a control condition with seated rest (normothermic). Brain temperature (Tbr), cerebral perfusion, and task-based brain activity were assessed using magnetic resonance imaging techniques. RESULTS: Tbr in motor cortex was found to be tightly regulated at rest (37.3°C ± 0.4°C (mean ± SD)) despite fluctuations in Tre. With the development of hyperthermia, Tbr increases and dovetails with the rising Tre. Bilateral motor cortical activity was suppressed during high-intensity plantarflexion tasks, implying a reduced central motor drive in hyperthermic participants (Tre = 38.5°C ± 0.1°C). Global gray matter perfusion and regional perfusion in sensorimotor cortex were reduced with passive hyperthermia. Executive function was poorer under a passive hyperthermic state, and this could relate to compromised visual processing as indicated by the reduced activation of left lateral-occipital cortex. Conversely, ingestion of blended ice before and during exercise alleviated the rise in both Tre and Tbr and mitigated heat-related neural perturbations. CONCLUSION: Severe heat exposure elevates Tbr, disrupts motor cortical activity and executive function, and this can lead to impairment of physical and cognitive performance.

ß subunits of voltage-gated calcium channels in cardiovascular diseases.

Calcium signaling is required in bodily functions essential for survival, such as muscle contractions and neuronal communications. Of note, the voltage-gated calcium channels (VGCCs) expressed on muscle and neuronal cells, as well as some endocrine cells, are transmembrane protein complexes that allow for the selective entry of calcium ions into the cells. The α1 subunit constitutes the main pore-forming subunit that opens in response to membrane depolarization, and its biophysical functions are regulated by various auxiliary subunits-ß, α2δ, and γ subunits. Within the cardiovascular system, the γ-subunit is not expressed and is therefore not discussed in this review. Because the α1 subunit is the pore-forming subunit, it is a prominent druggable target and the focus of many studies investigating potential therapeutic interventions for cardiovascular diseases. While this may be true, it should be noted that the direct inhibition of the α1 subunit may result in limited long-term cardiovascular benefits coupled with undesirable side effects, and that its expression and biophysical properties may depend largely on its auxiliary subunits. Indeed, the α2δ subunit has been reported to be essential for the membrane trafficking and expression of the α1 subunit. Furthermore, the ß subunit not only prevents proteasomal degradation of the α1 subunit, but also directly modulates the biophysical properties of the α1 subunit, such as its voltage-dependent activities and open probabilities. More importantly, various isoforms of the ß subunit have been found to differentially modulate the α1 subunit, and post-translational modifications of the ß subunits further add to this complexity. These data suggest the possibility of the ß subunit as a therapeutic target in cardiovascular diseases. However, emerging studies have reported the presence of cardiomyocyte membrane α1 subunit trafficking and expression in a ß subunit-independent manner, which would undermine the efficacy of ß subunit-targeting drugs. Nevertheless, a better understanding of the auxiliary ß subunit would provide a more holistic approach when targeting the calcium channel complexes in treating cardiovascular diseases. Therefore, this review focuses on the post-translational modifications of the ß subunit, as well as its role as an auxiliary subunit in modulating the calcium channel complexes.

Culprit versus non-culprit lesion related adverse cardiac events in patients with obstructive sleep apnoea.

BACKGROUND: In patients with obstructive sleep apnoea (OSA), the relative contribution of culprit versus non-culprit lesions to subsequent major adverse cardiac events (MACE) after acute myocardial infarction (AMI) remains unknown. Elucidating this relationship will shed light on the contributions of OSA to the advancement of coronary artery disease. METHODS: In a cohort of 105 patients who underwent an overnight sleep study after AMI, 98 were diagnosed with OSA (Apnoea-Hypopnoea Index (AHI) ≥5). The clinical outcomes at 5-year follow-up were determined. MACE was defined as a composite of cardiac death, reinfarction and repeat revascularisation. A culprit lesion was defined as the lesion involved in the initial AMI, and a non-culprit lesion as any lesion in the entire coronary tree outside the culprit lesion. RESULTS: Eighteen patients (median AHI: 28.1) developed MACE, of whom 12 presented with reinfarction and 6 with repeat revascularisation for stable angina. There was no cardiac death. Based on repeated coronary angiography, the MACE was related to the culprit lesion in 4 patients and the non-culprit lesion in 12 patients. The lesion responsible for the MACE was indeterminate in 2 patients, as coronary angiography was declined. The median duration from index AMI to culprit lesion-related and non-culprit lesion-related MACE were 10.5 and 20 months, respectively. CONCLUSIONS: The incidence of MACE among patients with OSA and AMI was 18.4%, and most of the events were related to non-culprit lesions rather than the culprit lesion during the initial AMI.