Lead-induced cardiomyocytes apoptosis by inhibiting gap junction intercellular communication via modulating the PKCα/Cx43 signaling pathway

Lead (Pb) is widely used in industrial production and easy to pollute the environment. It is one of the most common heavy metal contaminants in the environment. The risk of exposure to Pb contamination is everywhere. Human exposure routes include inhalation of Pb contaminated dust particles or aerosols and ingestion of Pb-contaminated food or water. Pb enters the human body through various ways, causing cardiovascular, central nervous system, kidney, and fertility problems and seriously harming human health [[1], [2], [3]]. The more environmentally polluted the areas are, the higher blood lead level of populations exposed to Pb [4]. In addition, studies have found that Pb can have cumulative toxic effects in the human body [5,6], So long-term exposure to low doses will also cause damage to the body. Epidemiological investigations in recent years have found that Pb exposure leads to abnormal cardiac function. With the increase of Pb exposure level, the risks of hypertension, coronary heart disease, atherosclerosis and other cardiovascular diseases increases, and the mortality rate of cardiovascular diseases also increases [[7], [8], [9], [10], [11]]. Pb exposure can also damage cardiac diastolic function, increases serum creatine kinase isoenzyme and lactate dehydrogenase (LDH) activities, and lead to extensive degeneration and necrosis of myocardium, muscle connection interruption, bleeding and monocyte infiltration and directly proportional to the blood Pb level [[12], [13], [14]]. Although many studies have shown that Pb has cardiovascular toxicity to rats and human beings, the mechanism remains elucidated, which is essential for preventing Pb toxicity.

Apoptosis is an important cellular process that regulates cell survival and death. Apoptotic death is the primary cell death mechanism of low-level Pb-induced nephrotoxicity in renal proximal tubule cells [15]. Chao Li [16] have reported that Pb inhibits Gap junction intercellular communication (GJIC) in H9c2 cells, When GJIC is down-regulated, it may lead damaged cells to lose the rescue signals provided by healthy cells, weaken the resistance of cells to the environment, and promote cell apoptosis, leading to cells damage [17,18]. However, the specific regulatory mechanism of Pb action on GJIC of cardiomyocytes remains to be fully elucidated.

GJIC is considered to play an important role in the regulation of cell functions and is indispensable in maintaining intracellular environmental homeostasis [19]. Gap junctions (GJs) are formed by connexin, six connexin subunits oligomerize to form of a hemichannel, which can mediate the exchange of molecules between the intracellular and extracellular milieu [20]. The structural and functional integrity of GJs is the basis for maintaining physiological processes such as normal cell growth, proliferation and differentiation. Connexins are tetra-span plasma membrane proteins that are the key structural component of cellular channels, GJs, formed between neighboring cells, and are critical roles in cell-cell communication, cells survival, proliferation, differentiation and patterning [21]. Connexin 43 (Cx43) is the main expression protein of GJs in cardiomyocytes, and changes in its number, distribution and phosphorylation level will lead to abnormal GJs in cardiomyocytes, thereby regulating a variety of biological functions, such as cell growth, differentiation and apoptosis [22,23]. PKCα regulates various steps in the Cx43 life cycle [24], and plays a major role in intercellular communication. At present, the study of Pb exposure on myocardial injury mostly focused on the increased inflammation and stimulation of oxidative stress induced by Pb exposure in cardiomyocytes [25,26], but paid less attention to the pathway of Pb effect on GJIC between cardiomyocytes. The impact of PKCα/Cx43 signaling pathway on GJIC and apoptosis of cardiomyocytes after Pb exposure have not been reported.

To explore the mechanism of cardiovascular system injury induced by Pb exposure, we hypothesized that Pb -induced cardiomyocytes apoptosis by inhibiting GJIC via modulating the PKCα/Cx43 signaling pathway. To test this hypothesis, we explored the regulation mechanism of Pb on GJIC. At the same time, the influence of Pb on the expression and phosphorylation of PKCα and Cx43 was explored to figure out its relationship with PKCα/Cx43 signaling pathway. The new mechanistic insight of Pb induced cardiomyocyte apoptosis from the present study would provide a new basis for developing valid therapies to combat a series of Pb -induced cardiovascular disease.

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