SERCA2a: its role in the development of heart failure and as a potential therapeutic target

Figures & data

Table 1 Potential drug therapies targeting SERCA2a for treatment of heart failure

Post-translational modification, protein, or drug	Activator or inhibitor	Sites in the protein or mechanism of action	References
Istaroxime	Activator	Favoring E1 SERCA2a conformation	38–47
Carvedilol	Activator	Increased Sp1 binding to SERCA2 promoter	48
Oxymatrine	Activator	Possibly through TNF-α inhibition or Sp1 induction	49–56
Acetylation	Unknown	K464, K510, and K533; possibly through	78,81,83–85
		SIRT1 or other deacetylases
Nitration	Inhibitor	Tyr294, Tyr295, and Tyr753	93–97
S-glutathiolation	Activator	Cys674	98
Egr-1	Inhibitor	Transcriptional repression	102,103,105
O-GlcNAcylation	Inhibitor	Sp1 and PLN modification	119,120,122,123

Abbreviations: Cys, cysteine; Egr-1, early growth response protein-1; PLN, phospholamban; SERCA2a, sarco/endoplasmic reticulum Ca²⁺ adenosine triphosphatase-2a; SIRT1, sirtuin-1; Sp1, specificity protein-1; TNF-α, tumor-necrosis factor-α; Tyr, tyrosine; O-GlcNAcylation, β-O-linkage of N-acetylglucosamine.

Table 2 SERCA2 gene therapy clinical trials for heart failure

Trial	Diseases	Route/vector	Stage	Number of patients
CUPID^Citation62–Citation66,Table Footnote*	Heart failure, congestive dilated cardiomyopathy	Intracoronary/AAV1-SERCA2a (MYDICAR^®)	Phase II, completed	51
AGENT-HF^Citation68,Table Footnote*	Heart failure, ischemic, and nonischemic	Intracoronary/AAV1-SERCA2a	Phase II, enrolling	44
SERCA2 Gene Therapy in LVAD patients^Citation69,Table Footnote*	Advanced heart failure with LVAD, ischemic, and nonischemic	Intracoronary/AAV6-SERCA2a	Phase II, enrolling	16
CUPID2^Citation67,Table Footnote*	Heart failure, ischemic, and nonischemic	Intracoronary/AAV1-SERCA2a (MYDICAR^®)	Phase IIb, enrolling	250

Note:

* From ClinicalTrials.gov. MYDICAR^®, Celladon Corporation, San Diego, CA, USA.

Abbreviations: AAV, adeno-associated virus; AGENT-HF, AAVI–cytomegalovirus-SERCA2a Gene Therapy Trial in Heart Failure; CUPID, Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease; LVAD, left ventricular assist device; SERCA2a, sarco/endoplasmic reticulum Ca²⁺ adenosine triphosphatase-2a.

Table 3 Possible gene therapies to modify SERCA2a activity or expression

Gene delivered	Mechanism of action	References
SERCA2a	Direct SERCA2a upregulation	57–69
Mutant PLN	Interference with wild type PLN-mediated inhibition	76
SUMO-1	Increased SERCA2a activity	78
miR-1	ET-1 repression and MAPK inhibition	125–126
S100A1	Increased SERCA2a activity	130–132

Abbreviations: ET-1, endothelin-1; MAPK, mitogen-activated protein kinase; PLN, phospholamban; SERCA2a, sarco/endoplasmic reticulum Ca²⁺ adenosine triphosphatase-2a; SUMO, Small ubiquitin-like modifier-1; miR-1, micro RNA-1.

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