Pathological implications of cellular stress in cardiovascular diseases

Cell degeneration and dysfunction are among the primary causes of numerous cardiovascular diseases, leading to tissue and cumulative organ collapse and decline. Such a phenomenon is even more prominent as we age. Cardiovascular diseases (CVDs) are a common co-morbidity of ageing-associated diseases (Suzman et al., 2015). The heart is the central regulator of the body, which must pump constantly to meet daily needs. In pathological conditions, the heart faces multiple cellular stresses such as mitochondrial stress, endoplasmic reticulum stress, replicative stress, and hypoxia. But the defence system undertakes countermeasures to neutralize the stress and restore the balance. However, at a certain point, excessive stress contributes to cardiac dysfunction. Knowledge of cellular stress is imperative for the successful development of a drug specific to the disease condition. Considering the importance of stress dynamics in pathology, this review focus on the mechanism of action of different organelle molecular stress response. There are unique molecular mechanisms in each organelle, but all these mechanisms interlink with one another to maintain body homeostasis. The mitochondria provide a vital source of cellular energy: adenosine triphosphate (ATP), nicotinamide adenine dinucleotide phosphate (NADPH), and NADP (Morales et al., 2020), meeting the cell’s daily demands. But impairment of mitochondria function causes an imbalance in reactive oxygen species (ROS) which results in premature apoptosis and activates other cellular responses. One of the active responses is endoplasmic reticular (ER) stress, which leads to the accumulation of misfolded and unfolded protein, leading to the activation of the unfolded protein response (UPR) pathway and autophagy, impairing cardiac contraction and relaxation. Cells undergo a spectrum of stress and are exposed to a multitude of stress-inducing elements which cause alterations in cellular functioning. In response to stress, cells generate countermeasures to maintain cellular balance. For example, when quality control mechanisms, like autophagy, are activated, damaged organelles (such as mitochondria) are cleared and new organelles are synthesized (Fulda et al., 2010). However, prolonged stress impairs the repair mechanisms of the cell and leads to the activation of cell death mechanisms (such as apoptosis, necrosis, etc.) (Jurivich and Zhou, 2007). Similarly, cells also face pathological stress conditions such as a lack of oxygen. Oxygen is essential for the heart to function properly, a decrease in normal oxygen supply (normoxia) is known as hypoxia. Under hypoxic conditions, the heart is kept under constant pressure to maintain the normal body environment, which further increases cellular stress in cardiac cells. All these processes lead to cell senescence or the development of tumorigenic properties. A cell’s fate is also determined by the crosstalk between stress response pathways.

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