Zinc and the prooxidant heart failure phenotype.
J Cardiovasc Pharmacol
; 64(4): 393-400, 2014 Oct.
Article
in En
| MEDLINE
| ID: mdl-25291496
ABSTRACT
Neurohormonal activation with attendant aldosteronism contributes to the clinical appearance of congestive heart failure (CHF). Aldosteronism is intrinsically coupled to Zn and Ca dyshomeostasis, in which consequent hypozincemia compromises Zn homeostasis and Zn-based antioxidant defenses that contribute to the CHF prooxidant phenotype. Ionized hypocalcemia leads to secondary hyperparathyroidism with parathyroid hormone-mediated Ca overloading of diverse cells, including cardiomyocytes. When mitochondrial Ca overload exceeds a threshold, myocyte necrosis follows. The reciprocal regulation involving cytosolic free [Zn]i as antioxidant and [Ca]i as prooxidant can be uncoupled in favor of Zn-based antioxidant defenses. Increased [Zn]i acts as a multifaceted antioxidant by (1) inhibiting Ca entry through L-type channels and hence cardioprotectant from the Ca-driven mitochondriocentric signal-transducer effector pathway to nonischemic necrosis, (2) serving as catalytic regulator of Cu/Zn-superoxide dismutase, and (3) activating its cytosolic sensor, metal-responsive transcription factor that regulates the expression of relevant antioxidant defense genes. Albeit present in subnanomolar range, increased cytosolic free [Zn]i enhances antioxidant capacity that confers cardioprotection. It can be achieved exogenously by ZnSO4 supplementation or endogenously using a ß3-receptor agonist (eg, nebivolol) that enhances NO generation to release inactive cytosolic Zn bound to metallothionein. By recognizing the pathophysiologic relevance of Zn dyshomeostasis in the prooxidant CHF phenotype and by exploiting the pharmacophysiologic potential of [Zn]i as antioxidant, vulnerable cardiomyocytes under assault from neurohormonal activation can be protected and the myocardium spared from adverse structural remodeling.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Zinc
/
Cardiotonic Agents
/
Oxidative Stress
/
Heart Failure
/
Antioxidants
Limits:
Animals
/
Humans
Language:
En
Journal:
J Cardiovasc Pharmacol
Year:
2014
Document type:
Article
Affiliation country:
Tunisia